Mesalamine Formulations Research Articles

Effect of postprandial gastric conditions on in vitro drug release from modified release mesalamine formulations

The effect of gastric prandial conditions on in vitro drug release from oral, locally acting, colon-targeted, mesalamine formulations has not been previously evaluated. In vitro dissolution of four mesalamine formulations were investigated using a USP II paddle apparatus. Fed gastric conditions were simulated under three consecutive phases of milk/buffer at different ratios to simulate changes in physicochemical, gastric composition during food digestion. Drug release was not observed from enteric coated preparations in the fasted state. Under simulative postprandial gastric conditions, however, drug release from Apriso® extended release (ER) capsules was 19 ± 4.7 %. As for Lialda® delayed release (DR) tablets, following two hours of exposure to simulative ileo-colonic media comprising bicarbonate buffer, drug release in the fed and fasted states was 55.7 ± 22.4 % and 12.4 ± 6.4 %, respectively. Significant differences in in vitro dissolution profiles were not observed between fasted and fed conditions for Pentasa® ER capsules and Asacol® HD DR tablets. Published pharmacokinetic data for Apriso and Lialda show higher systemic absorption of mesalamine in fed compared to fasted individuals. Our in vitro data is consistent with these pharmacokinetic findings since fed conditions may give rise to a higher extent of proximal drug release and therefore greater systemic absorption. Furthermore, extent of systemic exposure to mesalamine from Pentasa and Asacol was found not to be affected by food intake. In vitro dissolution studies simulating the gastric prandial state can possibly predict the impact of food on drug release from delayed and sustained release, locally acting formulations.

Formulation and Evaluation of Taste Masked Chewable Tablet containing Curcumin, Acetaminophen, and Ascorbic acid to treat sore throat

Objective: This study was intended to investigate the formulation and characterization of Mesalamine or 5-Aminosalicylic acid (5-ASA) pellets using novel excipient and formulated as matrix spheres to controlled the drug release extended period of time. Uniformly distributed throughout the gastrointestinal tract and Avoid dose dumping of drug. Methods: Mesalamine's active pharmaceutical component was characterised, and investigations were conducted prior to formulation to ensure a physical combination of the drug and excipients was achieved. Formulation of mesalamine as matrix pellets by using fluid bed processor and mesalamine loaded into seal coated sugar spheres and extended-release coating with Ethyl cellulose. Ethyl cellulose is pH independent polymer and retarder the drug release throughout the gastrointestinal tract and site-specific action in colon. Hypromellose also act as pore former and drug release based on diffusion mechanism. In drug layering, core pellets contain stearic acid and hydrogenated castor oil internally forming a matrix. Developed mesalamine pellets are characterized such as drug content, invitro drug release and appearances and particle size distribution. Results: Development of Mesalamine pellets based on five strategy From MEZ 1 to MEZ 5 are formulated and Characterization are performed. Based on the invitro drug release studies, we concluded that the formulation MEZ-IV was best formulation. Invitro drug release is consistence throughout 12hours.(1hrs-23%, 2nd hrs 41%, 4hrs-73, 6hrs-86, 8hrs-99% and 12hrs-10.

Modulation of mesalamine release from enteric-coated matrix tablets using natural polysaccharides for localized colonic delivery

Background: Inflammatory bowel diseases (IBD) require effective colon-targeted drug delivery for improved therapeutic efficacy and minimized systemic side effects. Objectives: The objective of this research was to develop and evaluate novel colon-targeted matrix tablet formulations of mesalamine (5-aminosalicylic acid) for the treatment of IBD. Materials and Methods: Mesalamine matrix tablets were prepared by wet granulation technique using pH-sensitive polymers (HPMC K4M) and biodegradable natural polysaccharides (pectin, chitosan, and guar gum). Tablets were characterized for physicochemical properties, drug content, and in vitro drug release. Compatibility studies using FTIR and DSC confirmed no interaction between mesalamine and polymers. The optimized formulations were enteric-coated with Eudragit S100 and ethyl cellulose. Drug release kinetics and stability studies were conducted. Results and Discussion: The uncoated formulations (M3, M6, M7) showed adequate protection against drug release in simulated gastric (0-2 h) and intestinal (2-5 h) fluids. The enteric-coated formulations (ME3, ME6, ME7) exhibited a lag time of around 2 hours and restricted drug release (<5%) in simulated gastric and intestinal fluids up to 5 hours. However, in simulated colonic fluid (pH 6.8) containing 4% rat cecal contents, these formulations showed enhanced drug release (71-83% in 12 h) due to biodegradation of polymeric matrices by colonic enzymes. Drug release kinetics indicated anomalous transport or super case-II transport mechanisms. Stability studies at 40°C/75% RH for 3 months revealed no significant changes. Conclusion: The developed colon-targeted mesalamine matrix tablets demonstrated the potential to protect the drug from release in the upper GIT while facilitating targeted drug delivery to the colon, which could improve therapeutic efficacy and minimize systemic side effects in the treatment of IBD.

Development of optimal in vitro release and permeation testing method for rectal suppositories

Currently there are no compendial assays for testing drug release from rectal suppositories. It is therefore essential to study different in vitro release testing (IVRT) and in vitro permeation testing (IVPT) methods for identifying a suitable technique to compare in vitro drug release and to predict in vivo performance of rectal suppositories. In the present study, three different rectal suppository formulations of mesalamine (CANASA, Generic, and In-house) were studied for in vitro bioequivalence. All the different suppository products were characterized by performing weight variation, content uniformity, hardness, melting time, and pH tests. Viscoelastic behavior of the suppositories was also tested both in presence and absence of mucin. Four different IVRT techniques such as Dialysis, Horizontal Ussing Chamber, Vertical Franz cell, and USP apparatus 4. IVPT studies were performed using Horizontal Ussing chamber and Vertical Franz cell methods. Q1/Q2 equivalent products (CANASA, Generic) and a half-strength product were studied to understand the reproducibility, bio relevance, and discriminatory ability of the IVRT and IVPT methods. This study is the first of its kind where molecular docking studies were performed to determine the potential interactions of drug (mesalamine) with mucin, IVRT studies were conducted with and without the presence of mucin, and porcine rectal mucosa was used to perform IVPT tests. The USP 4 method and Horizontal Ussing chamber methods were found to be suitable IVRT and IVPT techniques, respectfully, for rectal suppositories. RLD (Reference Listed Drug) and Generic rectal suppositories were found to exhibit similar release rate and permeation profiles obtained from USP 4, and the IVPT studies, respectfully. Wilcoxon Rank Sum/Mann-Whitney rank test, conducted for the IVRT profiles obtained using USP 4 method, proved the sameness of RLD and Generic suppository products.

Inflammatory Bowel Disease and Pregnancy

Inflammatory Bowel Disease and Pregnancy

Similar pharmacokinetics of three dosing regimens comprising two oral delayed-release mesalamine formulations in healthy adult volunteers: Randomised, open-label, parallel-group study.

AimsMesalamine is the first‐line therapy for treating mild‐to‐moderate ulcerative colitis. Multiple mesalamine formulations are available, with similar safety and efficacy profiles. Mesalamine is commonly administered as divided dosing, although once‐daily dosing may provide benefits for patients. We evaluated the pharmacokinetics of three dosing regimens of two oral delayed‐release mesalamine formulations in healthy adult volunteers.MethodsA randomised, open‐label, parallel‐group study of mesalamine pharmacokinetics following Lialda 2 × 1.2 g once daily (QD) (dose A), Asacol 6 × 400 mg QD (dose B), or Asacol 2 × 400 mg three times daily (TID) (dose C) over 7 days. Assessments included 5‐aminosalicylic acid (5‐ASA) and N‐acetyl 5‐aminosalicylic acid (N‐Ac‐5‐ASA, primary metabolite) pharmacokinetics (A e(%), AUC0‐24 and C max), safety and tolerability.ResultsAll enrolled volunteers (n = 37) completed the study. Steady state was achieved for all treatments by day 4. Ratios (95% CI) of means for steady‐state AUC0‐24 (dose A vs B 90.3% [39.8, 204.8], dose A vs C 123.5% [55.3, 275.7], dose B vs C 136.8% [61.3, 305.5]) and C max (dose A vs B 106.0% [46.4, 242.2], dose A vs C 133.0% [59.1, 299.0], dose B vs C 125.5% [55.8, 282.1]) were similar for all 5‐ASA treatments. Mean urinary excretion of 5‐ASA plus N‐Ac‐5‐ASA was comparable between treatments (dose A 21.3%, dose B 20.2%, dose C 17.9%). All treatment regimens were well tolerated; no safety issues were observed.ConclusionsPlasma and urine pharmacokinetics for Asacol TID, Asacol QD, and Lialda QD are similar, suggesting similar daily systemic exposures can be obtained with either TID or QD dosing. NCT00751699.

Multicenter survey on mesalamine intolerance in patients with ulcerative colitis.

Although oral mesalamine is the first-choice drug for treating mild-to-moderate ulcerative colitis (UC), some patients show symptoms of intolerance, including exacerbation of diarrhea and abdominal pain. The present study clarified the current state and clinical courses of patients with mesalamine intolerance. Patients who were diagnosed with UC and administered oral mesalamine at eight hospitals in Japan with a follow-up period exceeding 1year were analyzed. Sixty-seven (11%) of 633 patients showed intolerance to at least one formulation of oral mesalamine. The frequency of mesalamine intolerance has increased in recent years, rising from 5.3% in 2007-2010 to 9.1% in 2011-2013 and 16.2% in 2014-2016. The most common complications were the exacerbation of diarrhea (n=29), a fever (n=25), and abdominal pain (n=22). Readministration of mesalamine/sulfasalazine was attempted in 43 patients, mostly with other types of formulation of mesalamine, and more than half of these patients proved to be tolerant. The risk factors for mesalamine intolerance were female gender (odds ratio [OR]=1.83; 95% confidence interval [CI], 1.08-3.12), age<60years old (OR=2.82; CI, 1.19-8.33), and pancolitis (OR=2.09; 95% CI, 1.23-3.60). There were no significant differences in the use of anti-tumor necrosis factor-α agents, colectomy, or steroid-free remission at the last visit between patients with and without mesalamine intolerance. Mesalamine intolerance is not rare, and its frequency has been increasing recently. The prognosis of patients with mesalamine intolerance did not differ significantly from that of those without intolerance.

Maternal gestational exposure to di-butyl phthalate (DBP) from medications and birthweight of progeny

TPS 742: Adverse birth outcomes 1, Exhibition Hall, Ground floor, August 27, 2019, 3:00 PM - 4:30 PM Background: Birthweight, an important predictor of long-term morbidity, is affected by several environmental factors. Thus, birthweight can be used as an early indicator for adverse health conditions that are linked with suboptimal in-utero development, including those possibly caused by gestational exposures to environmental toxicants. Di-butyl phthalate (DBP) is used as an excipient in some mesalamine medications prescribed for treatment of inflammatory bowel disease (IBD), leading to extremely high exposures among patients. DBP is an endocrine disruptor, yet its effects on birthweight have not been conclusively elucidated. We evaluated whether maternal gestational use of DBP-containing medications is linked with alterations in birthweight of progeny. Methods: We conducted a population-based analysis of 546,432 singletons born in 1999-2015 in a large Israeli health fund. Medication dispensing, birthweight, and demographic data were abstracted from electronic medical records. Analyses were performed using generalized estimating equation (GEE) and generalized additive linear regression models. Results: 2,276 singletons were exposed to mesalamine medications during gestation, of which 162 were exposed to a mesalamine formulation with DBP. In models adjusted for sociodemographic factors and other known predictors of birthweight, maternal gestational use of DBP-containing mesalamine formulation was associated with a reduction of 132.0g [95% C.I.:-240.8,-23.1] in birthweight, whereas use of non-DBP mesalamine formulations was associated with a decrease of 77.8g [95% C.I.:-104.7,-51.0] as compared to singletons from mothers not treated with mesalamine. Additional adjustment for gestational age did not alter results. Conclusions: Maternal gestational use of DBP-containing mesalamine medications was associated with a reduction in birthweight, although some of the effect is likely attributed to the underlying IBD. Subsequent analyses will examine longer-term adverse developmental outcomes possibly associated with gestational pharmaceutical exposure to DBP and other phthalate congeners. Future studies should evaluate whether similar findings are observed with less extreme exposures that more closely reflect background environmental levels.

Spray dried formulation of mesalamine embedded with probiotic biomass for the treatment of ulcerative colitis: in-vitro and in-vivo studies

This study is using the targeted approach and anti-inflammatory action of the probiotic biomass to lessen the side effects of therapeutic agents of ulcerative colitis. The aim of the present study is to prepare mesalamine loaded eudragit S-100 with probiotic microparticles by spray drying method. The in-vitro release of the optimized formulation was 90.55 ± 2.42 in 24 hr, which display controlled drug release of mesalamine at a particular region. Mesalamine loaded eudragit S-100 with probiotic microparticles (F12) presented average particle size of 4.91 µm. The statistical analysis was done by one way ANOVA and then comparison test of Bonferroni was done and p values <.05 were considered as significant. The effects of spray dried microparticles over inflamed Caco-2 cell were also evaluated by determining the concentration of IL-8. From in-vivo study it was seen that pretreatment of mesalamine with probiotic prevents DNBS (Dinitrobenzenesulfonic acid) induced colitis in rats and represents protective action against ulcerative colitis because of its antioxidant and anti-inflammatory actions. The results give the foundation for a combination of targeted approach along with the anti-inflammatory potential of the probiotic which might help to decrease the problems which are seen with the traditional cure and management of ulcerative colitis.

Bioavailability and swallowability of an age-appropriate, delayed-release mesalamine formulation in healthy volunteers.

Objective: Delayed-release mesalamine 400 mg capsules containing four 100 mg tablets have been developed for children with ulcerative colitis who have difficulty swallowing. Bioavailability of the mesalamine capsules was compared with existing mesalamine tablets in healthy adults, and the effect of food on bioavailability from mesalamine capsules was determined. Tablet swallowability in healthy children was evaluated.Methods: In the open-label, replicate-treatment, single-dose, crossover, comparative bioavailability study, healthy adult volunteers were randomized to one of four treatment sequences to receive mesalamine 400 mg tablets (fasted) twice, mesalamine 400 mg capsules (fasted) twice, and a mesalamine 400 mg capsule (with food) once, with ≥7 days between treatments. Pharmacokinetic (PK) parameters were calculated and analyzed using the reference-scaled average bioequivalence procedure. In the open-label, single-dose swallowability study, healthy children aged 5–11 years were asked to swallow eight placebo tablets identical to those contained in two mesalamine capsules.Results: In the bioavailability study (n=160), mesalamine capsules and tablets in fasted volunteers exhibited similarly delayed absorption and were shown to be bioequivalent; statistical parameters calculated from PK values met the criteria for bioequivalence. A slight increase in mesalamine bioavailability was observed with food administration, but the delayed-release performance of the capsules was not affected. Overall safety profiles between capsules and tablets were similar. In the swallowability study (n=60), the majority of children swallowed eight placebo tablets, with slight variability between age groups.Conclusion: Evaluation of PK parameters confirmed mesalamine capsules are bioequivalent to mesalamine tablets. Mesalamine capsules were well tolerated, can be administered with or without food, and are an age-appropriate product for children.

High phthalate exposure increased urinary concentrations of quinolinic acid, implicated in the pathogenesis of neurological disorders: Is this a potential missing link?

BackgroundQuinolinic acid (QA), a neuroactive metabolite of the Kynurenine Pathway (KP), is an excitotoxin that is implicated in the pathogenesis of many neurological disorders. KP is the main tryptophan degradation pathway. Phthalates can structurally mimic tryptophan metabolites and diets containing phthalates in rats enhanced the production and excretion of QA. However, there are no human studies that have examined the association between phthalates and QA. ObjectivesTaking advantage of different mesalamine formulations with/without dibutyl phthalate (DBP), we assessed whether DBP from mesalamine (>1000x background) altered the urinary concentrations of QA. MethodsMen with inflammatory bowel disease participated in a prospective crossover pilot study. 15 Men were on non-DBP mesalamine (background) at baseline crossed-over for 4 months to high-DBP mesalamine (high) (B1H-Arm) and vice versa for 15 men who were on high-DBP mesalamine at baseline (H1B-Arm). Men provided 60 urine samples (2/man). We estimated crossover and cross-sectional changes in the creatinine normalized-QA using multivariable linear mixed effect models with random intercepts. ResultsAt baseline, men who were on high-DBP mesalamine (H1B-Arm) had 72%, (95% confidence interval (CI): 18, 151) higher normalized-QA than men who were on background exposure and when high-DBP mesalamine was removed for four months, normalized-QA decreased with 32%, (95% CI: −45.0, −15.1). Consistently, when men in B1H-Arm were newly-exposed to high-DBP mesalamine, normalized-QA increased with 11%, (95% CI: −11, 38). ConclusionsHigh-DBP exposure from mesalamine increased the urinary concentrations of QA, which was largely reversed after removal of the high-DBP exposure for four months. This novel hypothesis should warrant new promising research considering the KP and QA concentrations as a plausible mediator for the neurotoxicity possibly linked with phthalate exposures.

Formulation and Evaluation of Mesalamine Loaded pH Dependent Colon Specific Pulsatile Drug Delivery System

Formulation and Evaluation of Mesalamine Loaded pH Dependent Colon Specific Pulsatile Drug Delivery System

P389 Efficacy of once a day multi matrix mesalamine formulation, lialda in patients with active mild to moderate ulcerative colitis after inadequate response to the pH-dependent release mesalamine formulation, asacol

P389 Efficacy of once a day multi matrix mesalamine formulation, lialda in patients with active mild to moderate ulcerative colitis after inadequate response to the pH-dependent release mesalamine formulation, asacol

Mesalamine-Induced Nephrotoxicity Caused by Switch in Oral Formulation of Mesalamine in a Patient With Ulcerative Colitis: Case Report and Review of Literature

Mesalamine is widely used in the treatment of ulcerative colitis. Renal toxicity is one of the reported adverse reactions with the use of this medication. We report a case of renal toxicity resulting from a mandated formulary brand change of the medication in a patient who had tolerated long-term mesalamine therapy without complication. A 35-year-old Hawaiian man with past medical history of moderate pan-ulcerative colitis diagnosed in 1999 maintained on Lialda (once daily formulation of mesalamine which adopts a multi-matrix system of delivery), left testicular cancer status post left orchiectomy in 2006, appendectomy, and vasectomy was maintained in clinical remission with oral mesalamine and adjuvant biologic infliximab therapy. He denied a history of GI surgeries secondary to ulcerative colitis, history of hypertension, diabetes mellitus, nonsteroidal anti-inflammatory medications use or nephrolithiasis. Upon transition of his care from Hawaii to Texas, the patient developed acute renal failure with rise of creatinine to 2 mg/dL from a baseline of 1.2 mg/dL and positive urine eosinophils 2 weeks after a mandated formulary change in mesalamine preparation from Lialda to Apriso (once-daily delayed and extended-release dosage form of mesalamine). Apriso was stopped, nephrology consultation was obtained and the patient was questioned for any other possible etiology of this abrupt change. Thankfully, 1 week following cessation of Apriso, the patient's creatinine normalized to 1.3 mg/dL. A renal ultrasound was obtained which was unremarkable. Other potential and common causes of renal disease were effectively ruled out. Nephrology advised against returning to any mesalamine formulation in this clinical scenario and thus, the patient was not challenged with a return to Lialda. Mesalamine has generally been found to be a safe drug in the first-line treatment of ulcerative colitis. The wide safety margin of mesalamine may blur the differences between the two formulations. The systemic exposure to mesalamine, a 5-aminosalicylate (5-ASA) compound as measured by urinary excretion of total 5-ASA, and the fecal excretion of total 5-ASA is comparable for all oral mesalamine formulations and pro-drugs inferring that the side effect profile for mesalamine oral formulations should be equivalent. Our case is the first report to our knowledge of mesalamine-induced nephrotoxicity caused by a switch in oral formulation of mesalamine in a patient with ulcerative colitis. We hypothesize that this nephrotoxicity could have been secondary to variable drug metabolism and exposure to higher dose of active metabolites. This case illustrates the need to exercise caution when changing the oral formulation of mesalamine.

A crossover–crossback prospective study of dibutyl-phthalate exposure from mesalamine medications and serum reproductive hormones in men

BackgroundPhthalates, such as dibutyl phthalate (DBP), are endocrine disruptors used in some medication coatings e.g., mesalamine to treat inflammatory bowel disease (IBD). ObjectivesTaking advantage of different mesalamine formulations with/without DBP, we assessed whether DBP from mesalamine (>1000x background) altered serum hormones. MethodsMen (N=73) with IBD participated in a crossover-crossback prospective study and provided up to 6 serum samples (2:baseline, 2:crossover, 2:crossback). Men on non-DBP mesalamine (background) at baseline crossed-over for 4 months to DBP-mesalamine (high) and then crossed-back for 4 months to non-DBP mesalamine (B1HB2-arm) and vice versa for men on DBP-mesalamine at baseline (H1BH2-arm). We divided H1BH2-arm at the median (H1<3yrs or H1≥3yrs). We estimated crossover and crossback % changes in serum reproductive hormones using multivariable linear mixed effect models. ResultsWhen B1HB2-arm (26 men,134 samples) crossed-over, luteinizing hormone decreased 13.9% (95% confidence interval(CI): −23.6,−3.0) and testosterone, inhibin-B, and follicle-stimulating hormone (FSH) marginally decreased; after crossback all increased 8–14%. H1BH2-arm, H1≥3yrs (25 men,107samples) had no changes at crossover or crossback whereas in H1BH2-arm,H1<3yrs (22 men,100 samples) after crossover, inhibin-B increased 13.2% (CI: 4.2,22.9), FSH decreased 9.9% (CI: −17.9,−1.1) and after crossback, inhibin-B further increased 11.3%, and FSH marginally increased. ConclusionsHigh-DBP exposure may disrupt pituitary-gonadal hormones that largely reversed after exposure removal, but only in men with no or short previous high-exposure history. Paradoxically, men with longer duration of high-DBP exposure, exposure removal did not change hormone levels, suggesting that long-term high-DBP exposure may alter the pituitary-gonadal axis and make it insensitive to exposure changes.

Development and Evaluation of Mesalamine—Glutamine Cocrystal Tablets for Colon Specific Delivery

&#x0D; The objective of the work was to develop the co-crystal formulation of mesalamine with glutamine. It was done to enhance dissolution rate, solubility and physicochemical properties to be used in pharmaceutical composition (tablet) for colon targeting. Co-crystal preparation was carried out by liquid assisted grinding method using glutamine as a co-crystal former (1:1 stoichiometric ratio) and acetonitrile as a solvent giving maximum solubility and dissolution rate. The formation of the co-crystals was confirmed by Fourier Transform – Infra Red spectrometry, Differential Scanning Calorimetry and Powder X-Ray Diffraction. Pre-compression studies included measure-ment of bulk density, tapped density, angle of repose, Hausner’s ratio and compressibility index. The tablets were prepared by direct compression. Post compression parameters for uncoated tablets included hardness, size and thickness, friability and weight variation. Enteric-coated tablets were prepared by dip-coating process using Eudragit RSPO, Triethyl citrate and isopropyl alcohol mixture as coating solution. The coated tablets were further evaluated for disintegration and dissolution testing. All the results were found to be under specified limits. Finally, co-crystal tablets were compared with marketed formulation. In vitro dissolution rate of optimized mesalamine co-crystal tablet was comparatively higher than marketed formulation, which reflects improvement in solubility. Glutamine has good anti-inflammatory property. Formulation with glutamine as co-crystal added more efficacies to mesalamine for treatment in colon related inflammatory diseases. It was concluded that stable co-crystals of mesalamine -glutamine having better anti-inflammatory property, increased solubility and improved in vitro dissolution of mesalamine can be successfully prepared. &#x0D;

Measurement of in vivo Gastrointestinal Release and Dissolution of Three Locally Acting Mesalamine Formulations in Regions of the Human Gastrointestinal Tract.

As an orally administered, locally acting gastrointestinal drug, mesalamine products are designed to achieve high local drug concentration in the gastrointestinal (GI) tract for the treatment of ulcerative colitis. The aim of this study was to directly measure and compare drug dissolution of three mesalamine formulations in human GI tract and to correlate their GI concentration with drug concentration in plasma. Healthy human subjects were orally administered Pentasa, Apriso, or Lialda. GI fluids were aspirated from stomach, duodenum, proximal jejunum, mid jejunum, and distal jejunum regions. Mesalamine (5-ASA) and its primary metabolite acetyl-5-mesalamine (Ac-5-ASA) were measured using LC-MS/MS. GI tract pH was measured from each GI fluid sample, which averaged 1.82, 4.97, 5.67, 6.17, and 6.62 in the stomach, duodenum, proximal jejunum, middle jejunum, and distal jejunum, respectively. For Pentasa, high levels of 5-ASA in solution were observed in the stomach, duodenum, proximal jejunum, mid jejunum, and distal jejunum from 1 to 7 h. Apriso had minimal 5-ASA levels in stomach, low to medium levels of 5-ASA in duodenum and proximal jejunum from 4 to 7 h, and high levels of 5-ASA in distal jejunum from 3 to 7 h. In contrast, Lialda had minimal 5-ASA levels from stomach and early small intestine. A composite appearance rate (CAR) was calculated from the deconvolution of individual plasma concentration to reflect drug release, dissolution, transit, and absorption in the GI tract. Individuals dosed with Pentasa had high levels of CAR from 1 to 10 h; individuals dosed with Apriso had low levels of CAR from 1 to 4 h and high levels of CAR from 5 to 10 h; Lialda showed minimal levels of CAR from 0 to 5 h, then increased to medium levels from 5 to 12 h, and then decreased to further lower levels after 12 h. In the colon region, Pentasa and Apriso showed similar levels of accumulated 5-ASA excreted in the feces, while Lialda showed slightly higher 5-ASA accumulation in feces. However, all three formulations showed similar levels of metabolite Ac-5-ASA in the feces. These results provide direct measurement of drug dissolution in the GI tract, which can serve as a basis for investigation of bioequivalence for locally acting drug products.

A crossover–crossback prospective study of dibutyl-phthalate exposure from mesalamine medications and semen quality in men with inflammatory bowel disease

BackgroundPhthalates are widely used chemicals with ubiquitous exposure. Dibutyl-phthalate (DBP), a male reproductive toxicant in animals, is understudied in humans. Some mesalamine medications used to treat inflammatory bowel disease (IBD) have DBP in their coating, whereas other mesalamine formulations do not. ObjectivesTaking advantage of differences in mesalamine formulations, we investigated whether high-DBP exposure from mesalamine medications was associated with decreased semen parameters. Methods73 men with IBD taking mesalamine participated in a crossover-crossback prospective study. Men taking non-DBP containing mesalamine at baseline i.e., background exposure, crossed-over for four months to high-DBP mesalamine and then crossed-back for four months to their non-DBP mesalamine (B1HB2-arm;Background1-High-Background2) and vice versa for men taking high-DBP mesalamine at baseline (H1BH2-arm;High1-Background-High2). Men provided up to six semen samples (2: baseline, 2: crossover and 2: crossback). ResultsWe estimated crossover, crossback and carryover effects using linear mixed models adjusted for abstinence time, age, season and duration on high-DBP mesalamine at baseline. Semen parameters in B1HB2-arm (26 men, 133 samples) decreased after high-DBP mesalamine exposure (crossover versus baseline), especially motility parameters, and continued to decrease further even after crossback to non-DBP mesalamine (crossback versus crossover). The cumulative carryover effect of high-DBP (crossback versus baseline) was a decrease of % total sperm motility by 7.61(CI:−13.1, −2.15), % progressive sperm motility by 4.23(CI:−8.05, −0.4) and motile sperm count by 26.0% (CI:−46.2%, 1.7%). However, H1BH2-arm (47 men, 199 samples) had no significant change during crossover or crossback. ConclusionsMen newly exposed to high-DBP mesalamine for four months had a cumulative reduction in several semen parameters, primarily sperm motility, that was more pronounced and statistically significant even after exposure ended for four months.

A crossover–crossback prospective study of dibutyl-phthalate exposure from mesalamine medications and semen quality

Introduction: Phthalates are widely used chemicals with ubiquitous exposure. Dibutyl phthalate (DBP), a testicular toxicant in animals, is understudied in humans. Certain medications like Asacol®-mesalamine used to treat inflammatory bowel disease (IBD), contains DBP in its coating, whereas other mesalamine formulations do not. Taking advantage of this difference, we investigated whether high-DBP exposure from mesalamine medications was associated with poorer semen quality. Methods: We conducted a crossover-crossback prospective study in adult men with IBD. Men taking non-DBP containing mesalamine at baseline crossed over for 4 months to high-DBP mesalamine then crossed back for 4 months to their non-DBP mesalamine (LHL arm; Low-High-Low) and vice versa for men taking high-DBP mesalamine at baseline (HLH arm; High-Low-High). Men provided up to 6 semen samples (2 baseline, 2 crossover and 2 crossback). We estimated crossover, crossback and carryover effects using linear mixed models adjusted for abstinence time, age, season, and duration on high-DBP mesalamine at baseline. Results: Participants included 73 men (median age 31.6 years). Semen parameters in LHL arm (26 men, 133 samples) decreased after exposure to high-DBP mesalamine; %total sperm motility decreased (%TSM) by 4.2 (p=0.10), %progressive sperm motility (%PSM) by 1.8 (p=0.33), and motile sperm count (MSC) by 13.7% (p=0.32). Even after crossback to non-DBP mesalamine, %TSM further decreased by 3.4 (p=0.20), %PSM by 2.5 (p=0.19), and MSC by 14.3% (p=0.32). The cumulative carryover effect of high-DBP exposure for 4 months, was a decrease of %TSM by 7.6 (p=0.007), %PSM by 4.2 (p=0.03) and MSC by 26.0% (p=0.06). However, in HLH arm (47 men, 199 samples) there was no change in semen parameters during crossover or crossback. Conclusions: Men newly exposed to high-DBP mesalamine for 4 months had a cumulative reduction in semen quality that persisted for 4 months even after exposure ended.

Aminosalicylates for induction of remission or response in Crohn's disease.

Aminosalicylates for induction of remission or response in Crohn's disease.