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William J Sandborn - One of the best experts on this subject based on the ideXlab platform.

  • development of interim patient reported outcome measures for the assessment of ulcerative colitis disease activity in clinical trials
    Alimentary Pharmacology & Therapeutics, 2015
    Co-Authors: Vipul Jairath, William J Sandborn, Reena Khanna, Guangyong Zou, Larry Stitt, Mahmoud Mosli, Margaret K Vandervoort, Geert Dhaens
    Abstract:

    SummaryBackground Patient-reported outcomes (PROs) have an increasingly important role in the evaluation of new therapies for inflammatory bowel disease. The US Food and Drug Administration has issued formal guidance to describe the role of PRO instruments in evaluation of claims for product labelling. However, no validated PRO exists for ulcerative colitis. Aim To investigate whether the PROs from the Mayo Clinic Score (MCS) for UC can be modified, to develop an interim PRO for use in clinical trials, alone or in combination with endoscopy. Methods Data from an induction trial of a mesalazine (Mesalamine) formulation were used to compare effect sizes between mesalazine and placebo for PRO items (stool frequency and rectal bleeding) alone and in combination with endoscopy. The operating properties of the PRO were validated using data from a phase 2 trial of MLN02, a humanised antibody to the α4β7 integrin in patients with UC. Results A two-item PRO (PRO2) consisting of rectal bleeding = 0 and stool frequency ≤1 or ≤2, combined with an endoscopy subscore ≤1 yielded statistically significant differences between active drug and placebo. This combination yielded the most similar effect sizes and placebo rates for remission, compared to the primary trials. Use of PRO items alone yielded high placebo remission rates in both data sets, although rates were lower when the items were combined and remission defined as PRO2 = 0. Conclusion Patient-reported outcomes items derived from the Mayo Clinic Score combined with endoscopy as a co-primary endpoint may be an appropriate interim outcome measure for ulcerative colitis trials.

  • the role of centralized reading of endoscopy in a randomized controlled trial of Mesalamine for ulcerative colitis
    Gastroenterology, 2013
    Co-Authors: Brian G Feagan, William J Sandborn, Geert R Dhaens, Suresh Pola, John W D Mcdonald, Paul Rutgeerts, Pia Munkholm, Ulrich Mittmann, Debra King, Cindy J Wong
    Abstract:

    Background & Aims Interobserver differences in endoscopic assessments contribute to variations in rates of response to placebo in ulcerative colitis (UC) trials. We investigated whether centralized review of images could reduce these variations. Methods We performed a 10-week, randomized, double-blind, placebo-controlled study of 281 patients with mildly to moderately active UC, defined by an Ulcerative Colitis Disease Activity Index (UCDAI) sigmoidoscopy score ≥2, that evaluated the efficacy of delayed-release Mesalamine (Asacol 800-mg tablet) 4.8 g/day. Endoscopic images were reviewed by a single expert central reader. The primary outcome was clinical remission (UCDAI, stool frequency and bleeding scores of 0, and no fecal urgency) at week 6. Results The primary outcome was achieved by 30.0% of patients treated with Mesalamine and 20.6% of those given placebo, a difference of 9.4% (95% confidence interval [CI], −0.7% to 19.4%; P  = .069). Significant differences in results from secondary analyses indicated the efficacy of Mesalamine. Thirty-one percent of participants, all of whom had a UCDAI sigmoidoscopy score ≥2 as read by the site investigator, were considered ineligible by the central reader. After exclusion of these patients, the remission rates were 29.0% and 13.8% in the Mesalamine and placebo groups, respectively (difference of 15%; 95% CI, 3.5%–26.0%; P  = .011). Conclusions Although Mesalamine 4.8 g/day was not statistically different from placebo for induction of remission in patients with mildly to moderately active UC, based on an intent-to-treat analysis, the totality of the data supports a benefit of treatment. Central review of endoscopic images is critical to the conduct of induction studies in UC; ClinicalTrials.gov Number, NCT01059344.

  • once daily budesonide mmx extended release tablets induce remission in patients with mild to moderate ulcerative colitis results from the core i study
    Gastroenterology, 2012
    Co-Authors: William J Sandborn, Luigi Moro, Robert Bagin, Michael Huang, Simon Travis, Richard Jones, Theres Gautille, Philip Yeung, David E Ballard
    Abstract:

    Background & Aims Budesonide is a corticosteroid with minimal systemic corticosteroid activity due to first-pass hepatic metabolism. Budesonide MMX® is a once-daily oral formulation of budesonide that extends budesonide release throughout the colon using multi-matrix system (MMX) technology. Methods We performed a randomized, double-blind, double-dummy, placebo-controlled trial to evaluate the efficacy of budesonide MMX for induction of remission in 509 patients with active, mild to moderate ulcerative colitis (UC). Patients were randomly assigned to groups that were given budesonide MMX (9 mg or 6 mg), Mesalamine (2.4 g, as reference), or placebo for 8 weeks. The primary end point was remission at week 8. Results The rates of remission at week 8 among subjects given 9 mg or 6 mg budesonide MMX or Mesalamine were 17.9%, 13.2%, and 12.1%, respectively, compared with 7.4% for placebo ( P = .0143, P = .1393, and P = .2200). The rates of clinical improvement at week 8 among patients given 9 mg or 6 mg budesonide MMX or Mesalamine were 33.3%, 30.6%, and 33.9%, respectively, compared with 24.8% for placebo ( P = .1420, P = .3146, and P = .1189). The rates of endoscopic improvement at week 8 among subjects given 9 mg or 6 mg budesonide MMX or Mesalamine were 41.5%, 35.5%, and 33.1%, respectively, compared with 33.1% for placebo. The rates of symptom resolution at week 8 among subjects given 9 mg or 6 mg budesonide MMX or Mesalamine were 28.5%, 28.9%, and 25.0%, respectively, compared with 16.5% for placebo ( P = .0258, P = .0214, and P = .1025). Adverse events occurred at similar frequencies among groups. Conclusions Budesonide MMX (9 mg) was safe and more effective than placebo in inducing remission in patients with active, mild to moderate UC. ClinicalTrials.gov, Number: NCT00679432.

  • mmx multi matrix system mesalazine for the induction of remission in patients with mild to moderate ulcerative colitis a combined analysis of two randomized double blind placebo controlled trials
    Alimentary Pharmacology & Therapeutics, 2007
    Co-Authors: William J Sandborn, Gary R Lichtenstein, Michael A Kamm, Todd Butler, Andrew Lyne, Raymond E Joseph
    Abstract:

    Summary Background  MMX™ mesalazine [LIALDA™ (US), MEZAVANT™ XL (UK and Ireland) MEZAVANT™ (elsewhere)] utilizes MMX Multi Matrix System® (MMX) technology which delivers mesalazine throughout the colon. Two phase III studies have already evaluated MMX mesalazine in patients with active, mild-to-moderate ulcerative colitis. Aim  To provide more precise estimates of the efficacy of MMX mesalazine over placebo by combining the patient populations from the two phase III studies. Methods  Combined data from two 8-week, double-blind, placebo-controlled trials were analyzed. Patients randomized to MMX mesalazine 2.4 g/day (once daily or 1.2 g twice daily), 4.8 g/day (once daily) or placebo were reviewed. The primary end point was clinical and endoscopic remission (modified Ulcerative Colitis-Disease Activity Index of ≤1 calculated as: rectal bleeding and stool frequency scores of 0, a combined Physician’s Global Assessment and sigmoidoscopy score of ≤1, no mucosal friability and a ≥1-point reduction in sigmoidoscopy score from week 0). Results  Data from 517 patients were analysed. 8-week remission rates were 37.2% and 35.1% in the MMX mesalazine 2.4 g/day and 4.8 g/day groups, vs. 17.5% on placebo (P < 0.001, both comparisons). 8-week complete mucosal healing rates were 32% in both MMX mesalazine groups compared with 16% on placebo. Adverse event frequency was similar in all groups. Conclusion  MMX mesalazine is effective and generally well tolerated for inducing clinical and endoscopic remission of active, mild-to-moderate ulcerative colitis.

  • once daily high concentration mmx Mesalamine in active ulcerative colitis
    Gastroenterology, 2007
    Co-Authors: Michael A Kamm, William J Sandborn, Miguel A Gassull, Stefan Schreiber, Lechoslaw Jackowski, Todd Butler, Andrew Lyne, David Stephenson, Mary Palmen, Raymond E Joseph
    Abstract:

    Background & Aims: SPD476 (LIALDA™ in the US; MEZAVANT™ in the EU; otherwise known as MMX Mesalamine; Shire Pharmaceuticals Inc., Wayne, PA, under license from Giuliani SpA, Milan, Italy) is a novel, once-daily, high-strength (1.2 g/tablet) formulation of Mesalamine, utilizing MMX Multi Matrix System (MMX) technology designed to deliver the active drug throughout the colon. We performed a double-blind, multicenter study, comparing MMX Mesalamine vs placebo for the treatment of active ulcerative colitis. A delayed-release oral Mesalamine (ASACOL; Procter & Gamble, Cincinnati, OH) reference arm was included.Methods: Three hundred forty-three patients with active, mild-to-moderate ulcerative colitis received MMX Mesalamine 2.4 g/day or 4.8 g/day given once daily, ASACOL 2.4 g/day given in 3 divided doses, or placebo for 8 weeks. The primary end point was the proportion of patients in clinical and endoscopic remission (modified ulcerative colitis disease activity index of ≤1 with rectal bleeding and stool frequency scores of 0, no mucosal friability, and a ≥1-point reduction in sigmoidoscopy score from baseline). Results: A significantly greater proportion of patients receiving MMX Mesalamine 2.4 g/day given once daily (40.5%; P = .01) and 4.8 g/day given once daily (41.2%; P = .007) achieved clinical and endoscopic remission at week 8, vs placebo (22.1%). The clinical and endoscopic remission rate for ASACOL (32.6%; P = .124) was not significantly superior to placebo. All active treatments were well-tolerated. Conclusions: Once-daily MMX Mesalamine was efficacious and well-tolerated for the induction of clinical and endoscopic remission. MMX Mesalamine offers effective and convenient Mesalamine therapy, potentially improving treatment compliance.

Feiby L Nassan - One of the best experts on this subject based on the ideXlab platform.

  • high phthalate exposure increased urinary concentrations of quinolinic acid implicated in the pathogenesis of neurological disorders is this a potential missing link
    Environmental Research, 2019
    Co-Authors: Feiby L Nassan, Brent A Coull, Joshua Gunn, Melissa M Hill, Russ Hauser
    Abstract:

    Abstract Background Quinolinic 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. Objectives Taking advantage of different Mesalamine formulations with/without dibutyl phthalate (DBP), we assessed whether DBP from Mesalamine (>1000x background) altered the urinary concentrations of QA. Methods Men 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. Results At 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). Conclusions High-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.

  • dibutyl phthalate exposure from Mesalamine medications and serum thyroid hormones in men
    International Journal of Hygiene and Environmental Health, 2019
    Co-Authors: Feiby L Nassan, Brent A Coull, Niels E Skakkebaek, Stephen A Krawetz, Elizabeth J Hait, Joshua R Korzenik, Tim I M Korevaar, Molly Estill, Jennifer B Ford, Ralph A De Poortere
    Abstract:

    Abstract Background Dibutyl phthalate (DBP) is an endocrine disruptor and used in some medication coatings, such as Mesalamine for treatment inflammatory bowel disease (IBD). Objectives To determine whether high-DBP from some Mesalamine medications alters thyroid function. Methods Seventy men with IBD, without thyroid disease or any radiation history 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 exposure) at baseline crossed-over to DBP-Mesalamine (high exposure) then crossed-back to non-DBP Mesalamine (B1HB2-arm) and vice versa for men on DBP-Mesalamine at baseline (H1BH2-arm). Serum concentrations of total triiodothyronine (T3), total thyroxine (T4), free triiodothyronine (FT3), free thyroxine (FT4), thyroid-stimulating hormone (TSH) and thyroid peroxidase antibody (TPOAb), and thyroglobulin antibody (TgAb). Results After crossover in B1HB2-arm (26 men, 134 samples), T3 decreased 10% (95% confidence interval (CI): 14%,-5%), T3/T4 ratio decreased 8% (CI: 12%,-3%), TPOAb, and TgAb concentrations decreased, 11% (−20%, −2%) and 15% (−23%, −5%), respectively; after crossback, they increased. When men in the H1BH2-arm (44 men, 193 samples) crossed-over, T3 decreased 7% (CI: −11%, −2%) and T3/T4 ratio decreased 6% (CI: −9%, −2%). After crossback, only TgAb increased and FT4 decreased. Conclusions High-DBP novel exposure or removal from chronic high-DBP exposure could alter elements of the thyroid system, and most probably alters the peripheral T4 conversion to T3 and thyroid autoimmunity, consistent with thyroid disruption. After exposure removal, these trends were mostly reversed.

  • a crossover crossback prospective study of dibutyl phthalate exposure from Mesalamine medications and serum reproductive hormones in men
    Environmental Research, 2018
    Co-Authors: Feiby L Nassan, Brent A Coull, Niels E Skakkebaek, Michelle A Williams, Lidia Minguezalarcon, Stephen A Krawetz, Elizabeth J Hait, Annamaria Andersson, Janet E Hall, Joshua R Korzenik
    Abstract:

    Abstract Background Phthalates, such as dibutyl phthalate (DBP), are endocrine disruptors used in some medication coatings e.g., Mesalamine to treat inflammatory bowel disease (IBD). Objectives Taking advantage of different Mesalamine formulations with/without DBP, we assessed whether DBP from Mesalamine (>1000x background) altered serum hormones. Methods Men (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 Results When 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 Conclusions High-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.

  • a crossover crossback prospective study of dibutyl phthalate exposure from Mesalamine medications and semen quality in men with inflammatory bowel disease
    Environment International, 2016
    Co-Authors: Feiby L Nassan, Brent A Coull, Niels E Skakkebaek, Michelle A Williams, Ramace Dadd, Lidia Minguezalarcon, Stephen A Krawetz, Elizabeth J Hait, Joshua R Korzenik, Alan C Moss
    Abstract:

    Abstract Background Phthalates 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. Objectives Taking advantage of differences in Mesalamine formulations, we investigated whether high-DBP exposure from Mesalamine medications was associated with decreased semen parameters. Methods 73 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 (B 1 HB 2 -arm;Background 1 -High-Background 2 ) and vice versa for men taking high-DBP Mesalamine at baseline (H 1 BH 2 -arm;High 1 -Background-High 2 ). Men provided up to six semen samples (2: baseline, 2: crossover and 2: crossback). Results 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. Semen parameters in B 1 HB 2 -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, H 1 BH 2 -arm (47 men, 199 samples) had no significant change during crossover or crossback. Conclusions Men 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.

Gary R Lichtenstein - One of the best experts on this subject based on the ideXlab platform.

  • once daily Mesalamine formulation for maintenance of remission in ulcerative colitis a randomized placebo controlled clinical trial
    Journal of Clinical Gastroenterology, 2015
    Co-Authors: Glenn L Gordon, Salam Zakko, Uma Murthy, Shahriar Sedghi, Ronald Pruitt, Andrew C Barrett, Enoch Bortey, Craig Paterson, William P Forbes, Gary R Lichtenstein
    Abstract:

    Goals To evaluate the efficacy and safety of Mesalamine granules 1.5 g once daily for maintenance of ulcerative colitis (UC) remission. Background Mesalamine is a first-line treatment for induction and maintenance of UC remission. Study A phase 3, randomized, double-blind, placebo-controlled trial of patients with a history of mild to moderate UC, currently in remission, who received Mesalamine granules once daily for 6 months. The primary efficacy endpoint was percentage of patients maintaining UC remission at 6 months. Results A significantly greater percentage of patients receiving Mesalamine granules versus placebo were in remission at 6 months (79.9% vs. 66.7%; P=0.03). A greater percentage of patients receiving Mesalamine granules maintained a revised Sutherland Disease Activity Index (SDAI)≤2 with no individual component of revised SDAI>1 and rectal bleeding=0 at 6 months (72.0% vs. 58.1%; P=0.04). No significant differences between groups were observed for change from baseline to 6 months for total SDAI score or its components (ie, stool frequency, rectal bleeding, mucosal appearance, physician's rating of disease). Mesalamine granules treatment resulted in a significantly longer remission duration versus placebo (P=0.02) and decreased patients' risk of relapse by 43% (hazard ratio=0.57; 95% confidence interval, 0.35-0.93; P=0.02). Mesalamine granules were well tolerated, and adverse events related to hepatic, renal, and pancreatic function-potential concerns with long-term treatment-occurred at a rate similar to placebo. Conclusions Once-daily Mesalamine granules are efficacious and safe for the maintenance of UC remission.

  • review article delivery and efficacy of topical 5 aminosalicylic acid mesalazine therapy in the treatment of ulcerative colitis
    Alimentary Pharmacology & Therapeutics, 2011
    Co-Authors: M S Harris, Gary R Lichtenstein
    Abstract:

    Aliment Pharmacol Ther 2011; 33: 996–1009 Summary Background  The use of topical therapy in the treatment of ulcerative colitis has declined in recent years despite evidence of good efficacy. Aims  To review US prescription trends for 5-aminosalicylic acid (5-ASA) since the US approval of Asacol extended-release oral mesalazine (Mesalamine) in 1992; to estimate the optimal level of 5-ASA exposure in the distal colon; to determine factors influencing distal colonic exposures; and to compare the effectiveness of different 5-ASA formulations (oral, topical suspension, foam, suppositories) in clinical trials. Methods  Review of clinical trials, physiologic studies and prescription trends of various mesalazine formulations for treatment of distal ulcerative colitis. Results  Between 1992 and 2009, prescriptions for oral mesalazine increased sixfold, whereas topical suspensions declined by 10%. In clinical trials, topical therapy resulted in higher remission and clinical response rates than oral therapy, with trends to earlier improvement. The mucosal concentrations of 5-ASA achieved by topical agents in the distal colon were up to 200-fold higher than those achieved by oral administration alone. Despite active colitis, over 40% of a topically administered 4 g 5-ASA suspension (equal to 1.6 g) reached the sigmoid colon. This likely represents a therapeutic exposure of 5-ASA. Although topical therapies are less convenient than oral medications, treatment algorithms have failed to take into account quality of life improvements resulting from more rapid and complete treatment response. Conclusions  Topical mesalazine therapy is superior to oral therapy in distal ulcerative colitis for both therapeutic response and drug delivery. Practice patterns should be re-evaluated in light of this information.

  • mmx multi matrix system mesalazine for the induction of remission in patients with mild to moderate ulcerative colitis a combined analysis of two randomized double blind placebo controlled trials
    Alimentary Pharmacology & Therapeutics, 2007
    Co-Authors: William J Sandborn, Gary R Lichtenstein, Michael A Kamm, Todd Butler, Andrew Lyne, Raymond E Joseph
    Abstract:

    Summary Background  MMX™ mesalazine [LIALDA™ (US), MEZAVANT™ XL (UK and Ireland) MEZAVANT™ (elsewhere)] utilizes MMX Multi Matrix System® (MMX) technology which delivers mesalazine throughout the colon. Two phase III studies have already evaluated MMX mesalazine in patients with active, mild-to-moderate ulcerative colitis. Aim  To provide more precise estimates of the efficacy of MMX mesalazine over placebo by combining the patient populations from the two phase III studies. Methods  Combined data from two 8-week, double-blind, placebo-controlled trials were analyzed. Patients randomized to MMX mesalazine 2.4 g/day (once daily or 1.2 g twice daily), 4.8 g/day (once daily) or placebo were reviewed. The primary end point was clinical and endoscopic remission (modified Ulcerative Colitis-Disease Activity Index of ≤1 calculated as: rectal bleeding and stool frequency scores of 0, a combined Physician’s Global Assessment and sigmoidoscopy score of ≤1, no mucosal friability and a ≥1-point reduction in sigmoidoscopy score from week 0). Results  Data from 517 patients were analysed. 8-week remission rates were 37.2% and 35.1% in the MMX mesalazine 2.4 g/day and 4.8 g/day groups, vs. 17.5% on placebo (P < 0.001, both comparisons). 8-week complete mucosal healing rates were 32% in both MMX mesalazine groups compared with 16% on placebo. Adverse event frequency was similar in all groups. Conclusion  MMX mesalazine is effective and generally well tolerated for inducing clinical and endoscopic remission of active, mild-to-moderate ulcerative colitis.

Joshua R Korzenik - One of the best experts on this subject based on the ideXlab platform.

  • dibutyl phthalate exposure from Mesalamine medications and serum thyroid hormones in men
    International Journal of Hygiene and Environmental Health, 2019
    Co-Authors: Feiby L Nassan, Brent A Coull, Niels E Skakkebaek, Stephen A Krawetz, Elizabeth J Hait, Joshua R Korzenik, Tim I M Korevaar, Molly Estill, Jennifer B Ford, Ralph A De Poortere
    Abstract:

    Abstract Background Dibutyl phthalate (DBP) is an endocrine disruptor and used in some medication coatings, such as Mesalamine for treatment inflammatory bowel disease (IBD). Objectives To determine whether high-DBP from some Mesalamine medications alters thyroid function. Methods Seventy men with IBD, without thyroid disease or any radiation history 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 exposure) at baseline crossed-over to DBP-Mesalamine (high exposure) then crossed-back to non-DBP Mesalamine (B1HB2-arm) and vice versa for men on DBP-Mesalamine at baseline (H1BH2-arm). Serum concentrations of total triiodothyronine (T3), total thyroxine (T4), free triiodothyronine (FT3), free thyroxine (FT4), thyroid-stimulating hormone (TSH) and thyroid peroxidase antibody (TPOAb), and thyroglobulin antibody (TgAb). Results After crossover in B1HB2-arm (26 men, 134 samples), T3 decreased 10% (95% confidence interval (CI): 14%,-5%), T3/T4 ratio decreased 8% (CI: 12%,-3%), TPOAb, and TgAb concentrations decreased, 11% (−20%, −2%) and 15% (−23%, −5%), respectively; after crossback, they increased. When men in the H1BH2-arm (44 men, 193 samples) crossed-over, T3 decreased 7% (CI: −11%, −2%) and T3/T4 ratio decreased 6% (CI: −9%, −2%). After crossback, only TgAb increased and FT4 decreased. Conclusions High-DBP novel exposure or removal from chronic high-DBP exposure could alter elements of the thyroid system, and most probably alters the peripheral T4 conversion to T3 and thyroid autoimmunity, consistent with thyroid disruption. After exposure removal, these trends were mostly reversed.

  • a crossover crossback prospective study of dibutyl phthalate exposure from Mesalamine medications and serum reproductive hormones in men
    Environmental Research, 2018
    Co-Authors: Feiby L Nassan, Brent A Coull, Niels E Skakkebaek, Michelle A Williams, Lidia Minguezalarcon, Stephen A Krawetz, Elizabeth J Hait, Annamaria Andersson, Janet E Hall, Joshua R Korzenik
    Abstract:

    Abstract Background Phthalates, such as dibutyl phthalate (DBP), are endocrine disruptors used in some medication coatings e.g., Mesalamine to treat inflammatory bowel disease (IBD). Objectives Taking advantage of different Mesalamine formulations with/without DBP, we assessed whether DBP from Mesalamine (>1000x background) altered serum hormones. Methods Men (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 Results When 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 Conclusions High-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.

  • a crossover crossback prospective study of dibutyl phthalate exposure from Mesalamine medications and semen quality in men with inflammatory bowel disease
    Environment International, 2016
    Co-Authors: Feiby L Nassan, Brent A Coull, Niels E Skakkebaek, Michelle A Williams, Ramace Dadd, Lidia Minguezalarcon, Stephen A Krawetz, Elizabeth J Hait, Joshua R Korzenik, Alan C Moss
    Abstract:

    Abstract Background Phthalates 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. Objectives Taking advantage of differences in Mesalamine formulations, we investigated whether high-DBP exposure from Mesalamine medications was associated with decreased semen parameters. Methods 73 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 (B 1 HB 2 -arm;Background 1 -High-Background 2 ) and vice versa for men taking high-DBP Mesalamine at baseline (H 1 BH 2 -arm;High 1 -Background-High 2 ). Men provided up to six semen samples (2: baseline, 2: crossover and 2: crossback). Results 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. Semen parameters in B 1 HB 2 -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, H 1 BH 2 -arm (47 men, 199 samples) had no significant change during crossover or crossback. Conclusions Men 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.

Brent A Coull - One of the best experts on this subject based on the ideXlab platform.

  • high phthalate exposure increased urinary concentrations of quinolinic acid implicated in the pathogenesis of neurological disorders is this a potential missing link
    Environmental Research, 2019
    Co-Authors: Feiby L Nassan, Brent A Coull, Joshua Gunn, Melissa M Hill, Russ Hauser
    Abstract:

    Abstract Background Quinolinic 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. Objectives Taking advantage of different Mesalamine formulations with/without dibutyl phthalate (DBP), we assessed whether DBP from Mesalamine (>1000x background) altered the urinary concentrations of QA. Methods Men 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. Results At 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). Conclusions High-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.

  • dibutyl phthalate exposure from Mesalamine medications and serum thyroid hormones in men
    International Journal of Hygiene and Environmental Health, 2019
    Co-Authors: Feiby L Nassan, Brent A Coull, Niels E Skakkebaek, Stephen A Krawetz, Elizabeth J Hait, Joshua R Korzenik, Tim I M Korevaar, Molly Estill, Jennifer B Ford, Ralph A De Poortere
    Abstract:

    Abstract Background Dibutyl phthalate (DBP) is an endocrine disruptor and used in some medication coatings, such as Mesalamine for treatment inflammatory bowel disease (IBD). Objectives To determine whether high-DBP from some Mesalamine medications alters thyroid function. Methods Seventy men with IBD, without thyroid disease or any radiation history 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 exposure) at baseline crossed-over to DBP-Mesalamine (high exposure) then crossed-back to non-DBP Mesalamine (B1HB2-arm) and vice versa for men on DBP-Mesalamine at baseline (H1BH2-arm). Serum concentrations of total triiodothyronine (T3), total thyroxine (T4), free triiodothyronine (FT3), free thyroxine (FT4), thyroid-stimulating hormone (TSH) and thyroid peroxidase antibody (TPOAb), and thyroglobulin antibody (TgAb). Results After crossover in B1HB2-arm (26 men, 134 samples), T3 decreased 10% (95% confidence interval (CI): 14%,-5%), T3/T4 ratio decreased 8% (CI: 12%,-3%), TPOAb, and TgAb concentrations decreased, 11% (−20%, −2%) and 15% (−23%, −5%), respectively; after crossback, they increased. When men in the H1BH2-arm (44 men, 193 samples) crossed-over, T3 decreased 7% (CI: −11%, −2%) and T3/T4 ratio decreased 6% (CI: −9%, −2%). After crossback, only TgAb increased and FT4 decreased. Conclusions High-DBP novel exposure or removal from chronic high-DBP exposure could alter elements of the thyroid system, and most probably alters the peripheral T4 conversion to T3 and thyroid autoimmunity, consistent with thyroid disruption. After exposure removal, these trends were mostly reversed.

  • a crossover crossback prospective study of dibutyl phthalate exposure from Mesalamine medications and serum reproductive hormones in men
    Environmental Research, 2018
    Co-Authors: Feiby L Nassan, Brent A Coull, Niels E Skakkebaek, Michelle A Williams, Lidia Minguezalarcon, Stephen A Krawetz, Elizabeth J Hait, Annamaria Andersson, Janet E Hall, Joshua R Korzenik
    Abstract:

    Abstract Background Phthalates, such as dibutyl phthalate (DBP), are endocrine disruptors used in some medication coatings e.g., Mesalamine to treat inflammatory bowel disease (IBD). Objectives Taking advantage of different Mesalamine formulations with/without DBP, we assessed whether DBP from Mesalamine (>1000x background) altered serum hormones. Methods Men (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 Results When 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 Conclusions High-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.

  • a crossover crossback prospective study of dibutyl phthalate exposure from Mesalamine medications and semen quality in men with inflammatory bowel disease
    Environment International, 2016
    Co-Authors: Feiby L Nassan, Brent A Coull, Niels E Skakkebaek, Michelle A Williams, Ramace Dadd, Lidia Minguezalarcon, Stephen A Krawetz, Elizabeth J Hait, Joshua R Korzenik, Alan C Moss
    Abstract:

    Abstract Background Phthalates 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. Objectives Taking advantage of differences in Mesalamine formulations, we investigated whether high-DBP exposure from Mesalamine medications was associated with decreased semen parameters. Methods 73 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 (B 1 HB 2 -arm;Background 1 -High-Background 2 ) and vice versa for men taking high-DBP Mesalamine at baseline (H 1 BH 2 -arm;High 1 -Background-High 2 ). Men provided up to six semen samples (2: baseline, 2: crossover and 2: crossback). Results 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. Semen parameters in B 1 HB 2 -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, H 1 BH 2 -arm (47 men, 199 samples) had no significant change during crossover or crossback. Conclusions Men 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.