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Ryuji Ueno - One of the best experts on this subject based on the ideXlab platform.
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Lubiprostone increases spontaneous bowel movement frequency and quality of life in patients with chronic idiopathic constipation
Clinical Gastroenterology and Hepatology, 2015Co-Authors: Shin Fukudo, Michio Hongo, Hiroshi Kaneko, Masahiro Takano, Ryuji UenoAbstract:Background & Aims Lubiprostone is an activator of the type 2 chloride channel that facilitates spontaneous bowel movement (SBM). We performed phase 3 studies to determine whether Lubiprostone increases the frequency of SBM in patients with chronic idiopathic constipation (CIC) in Japan, and whether long-term administration of Lubiprostone increases the quality of life of patients with CIC. Methods We performed a randomized, double-blind, placebo-controlled, phase 3 trial of Lubiprostone. Patients with CIC (n = 124) were assigned randomly to groups given placebo (n = 62) or Lubiprostone (48 μg/day; n = 62) for 4 weeks. The primary efficacy end point was the change from baseline in the weekly average number of SBMs after 1 week of administration. In a long-term study of efficacy and safety, 209 patients with CIC were given Lubiprostone (24 μg twice daily) for 48 weeks. Results Daily administration of Lubiprostone induced a significantly greater change, from baseline, in the weekly average number of SBMs at week 1 (increase of 3.7 ± 2.8), compared with placebo (increase of 1.3 ± 1.8; P P Conclusions In phase 3 studies in Japan, Lubiprostone increased the weekly average number of SBMs and increased the quality of life of patients with CIC. Clinical Trial Notification of the Japanese Regulatory Authorities: 20-3296 and 20-3300.
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a randomized study of Lubiprostone for opioid induced constipation in patients with chronic noncancer pain
Pain Medicine, 2014Co-Authors: Byron L Cryer, Seymour Katz, Ricardo Vallejo, Anca Popescu, Ryuji UenoAbstract:Objective To evaluate the efficacy and safety of oral Lubiprostone for relieving symptoms of opioid-induced constipation (OIC) in patients with chronic noncancer pain. Design Prospective, randomized, double-blind, placebo-controlled trial. Setting Seventy-nine US and Canadian centers. Subjects Patients aged ≥18 years with OIC, defined as <3 spontaneous bowel movements (SBMs) per week. Methods Patients received Lubiprostone 24 mcg or placebo twice daily for 12 weeks. The primary endpoint was change from baseline in SBM frequency at week 8. Results Among randomized patients (N = 418; Lubiprostone, N = 210; placebo, N = 208), most completed the study (Lubiprostone, 67.1%; placebo, 69.7%). The safety and efficacy (intent-to-treat) populations included 414 (Lubiprostone, N = 208; placebo, N = 206) and 413 (Lubiprostone, N = 209; placebo, N = 204) patients, respectively. The mean (standard deviation) age was 50.4 (10.9) years; most patients were female (64.4%) and white (77.7%). Changes from baseline in SBM frequency rates were significantly higher at week 8 (P = 0.005) and overall (P = 0.004) in patients treated with Lubiprostone compared with placebo. Pairwise comparisons showed significantly greater overall improvement for abdominal discomfort (P = 0.047), straining (P < 0.001), constipation severity (P = 0.007), and stool consistency (P < 0.001) with Lubiprostone compared with placebo. Moreover, patients rated the effectiveness of Lubiprostone as significantly (P < 0.05) better than placebo for 11 of 12 weeks. The most common treatment-related adverse events (AEs) with Lubiprostone and placebo were nausea (16.8% vs 5.8%, respectively), diarrhea (9.6% vs 2.9%), and abdominal distention (8.2% vs 2.4%). No Lubiprostone-related serious AEs occurred. Conclusion Lubiprostone effectively relieved OIC and associated signs and symptoms and was well tolerated in patients with chronic noncancer pain (http://clinicaltrials.gov/ct2/show/NCT00595946).
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Lubiprostone (a prostone) slows the in vitro growth of colon adenosarcoma cells with low [NAD+] 15-OH PGDH (LB856)
The FASEB Journal, 2014Co-Authors: John Cuppoletti, Jayati Chakrabarti, Kirti P Tewari, Danuta H Malinowska, Ryuji UenoAbstract:Objective. Lubiprostone is a bicyclic fatty acid (prostone) which is used widely for treatment of chronic idiopathic constipation (CIC), opioid-induced constipation (OIC) and constipation-associated irritable bowel syndrome (IBS-C). [NAD+]-15-OH PGDH (PGDH), which synthesizes endogenous prostones from prostaglandins, is a suppressor of human gastrointestinal cancers and genetic therapy with PGDH slowed the growth of colon tumor xenographs. The present study was to determine whether Lubiprostone, acting as a prostone, would slow growth of colon cancer cells which express low PGDH and whether transfection of low PGDH colon cancer cells with PGDH would ablate the effects of Lubiprostone on the cancer cells. Methods. LS174T (colon adenosarcoma) cells that contain low PGDH were grown in Eagle’s MEM/10% FBS, transfected with human PGDH cDNA in pCMV6-Entry vector or vector alone using Lipofectamine and selected using G418 (200 µg/ml). PGDH:GAPDH levels were determined by densitometry of western blots. LS174T cel...
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(452) Efficacy of Lubiprostone for the treatment of opioid-induced constipation according to opioid class
The Journal of Pain, 2014Co-Authors: Lynn R Webster, Shadreck M. Mareya, Randall P Brewer, A. Popescu, Ryuji UenoAbstract:s The Journal of Pain S89 (452) Efficacy of Lubiprostone for the treatment of opioidinduced constipation according to opioid class L Webster, A Popescu, R Brewer, S Mareya, and R Ueno; (pooled analysis of multicenter studies) Lubiprostone 24 mcg twice daily (BID) recently received US Food and Drug Administration approval for treating opioid-induced constipation (OIC) in patients with chronic non-cancer pain who are taking full-agonist opioids other than diphenylheptanes (eg, methadone). This first presentation of efficacy and safety results by opioid class from the Lubiprostone OIC program uses data pooled from three Phase 3, randomized, double-blind, placebocontrolled, 12-week studies. Efficacy was assessed by mean change from baseline (CFB) in frequency of spontaneous bowel movements (SBMs) at the pre-specifiedweek 8 timepoint in patients receiving phenanthrenes (eg, oxycodone, morphine, hydromorphone, and oxymorphone), phenylpiperidines (eg, fentanyl), or diphenylheptanes. Patients taking phenanthrenes and phenylpiperidines concurrently were counted in both groups; patients taking a diphenylheptane were analyzed only in that group. Demographic characteristics reflected clinical practice in patients receiving phenanthrenes (Lubiprostone: 63% female, 93%
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PTH-196 Lubiprostone Demonstrates Efficacy in Adult Patients with Constipation Regardless of age, Gender or Race
Gut, 2013Co-Authors: R Panas, Taryn Joswick, Gayle Dolecek, P Lichtlen, D Panigrahi, Ryuji UenoAbstract:Introduction Constipation is a common condition affecting millions globally. Lubiprostone has demonstrated safety and efficacy in treating adults with chronic idiopathic constipation. Through an analysis of the subgroups of two Phase 3 studies, the efficacy of Lubiprostone based on factors such as age, gender, and race was reviewed. Aims and Methods Combined data from two Phase 3 well-controlled studies were used to analyse the following subpopulations: non-elderly ( Results Among non-elderly patients, Lubiprostone produced a greater increase (p≤0.001) in SBM frequency each week over placebo. Statistically significant increases were observed in the elderly (p = 0.0188 to p = 0.0268) at each week except Week 2 (p = 0.0806). Statistically significant improvements were noted in females (p≤0.001) at all weeks and in males at all weeks (p = 0.0115 to p = 0.0500) except Week 3 (p = 0.0758). For non-whites (p = 0.0003 to p = 0.0021) and whites (p≤0.001), statistically significant increases in SBM frequencies were reported at all weeks. Table 1 shows the weekly change in SBM frequency for each group. Stool consistency was improved with Lubiprostone in the non-elderly (p = 0.0172 to p = 0.0441) and the elderly (p≤0.001) at all weeks. Straining was also improved with Lubiprostone treatment at all weeks in non-elderly patients (p≤0.001), with similar improvement trends observed in the elderly. Stool consistency and straining were statistically significantly improved with Lubiprostone at all weeks (p≤0.001) in females. A similar trend was observed for males but did not achieve statistical significance at all weeks. Lubiprostone improved stool consistency at all weeks in whites (p≤0.001) and non-whites (p≤0.0001 to p = 0.0006). Straining was improved at all weeks for whites (p≤0.001) and non-whites (p≤0.0001 to p = 0.0144). Conclusion Treatment with Lubiprostone resulted in increased SBM frequencies and improvement in related symptoms in patients with chronic idiopathic constipation regardless of age, gender, or race. Disclosure of Interest None Declared.
Jonathan D. Kaunitz - One of the best experts on this subject based on the ideXlab platform.
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may the truth be with you Lubiprostone as ep receptor agonist clc 2 internalizing inhibitor
Digestive Diseases and Sciences, 2012Co-Authors: Y Akiba, Jonathan D. KaunitzAbstract:Chronic constipation is a common clinical problem. Lubiprostone, a bicyclic fatty acid derived from prostaglandin (PG) E1, has been clinically used for the treatment of chronic constipation in adults. Camilleri et al. [1] first reported that Lubiprostone inhibited gastric emptying, but accelerated small and large intestinal transit, which is associated with postprandial fullness. Subsequently, on the basis of clinical trials, investigators have reported a beneficial effect of Lubiprostone in subjects with chronic constipation and functional bowel disease [2, 3]. Lubiprostone was marketed as belonging to a new therapeutic class, working by a mechanism described as a ClC-2 chloride channel activator. Cuppoletti et al. [4] first reported that Lubiprostone increased Cl secretion by activation of the intestinal epithelial cell ClC-2 channel, localized on the apical membrane of enterocytes. Since epithelial Cl secretion is mainly mediated by the cystic fibrosis transmembrane conductance regulator (CFTR) [5], mutations of which cause the disease cystic fibrosis (CF), enhancement of CFTR-independent Cl secretion has been explored as a rescue treatment for CF. Mice with the CFTR mutation DF508, the most common mutation observed in CF patients [6], and CFTR knockout (KO) exhibit an intestinal phenotype, i.e., intestinal obstruction due to loss of Cl secretion, enhancing their utility as models of CF [7]. Nevertheless, the cellular localization and functional roles of epithelial ClC-2 channel and the mechanism of Lubiprostone effects on Cl secretion have been questioned. First described in 1992 [8], ClC-2 channels are expressed in the stomach, intestine, colon, brain, heart, and muscles. ClC-2 was first proposed to provide a pathway for epithelial Cl secretion, in addition to CFTR [9]. This hypothesis, however, is not supported by the observation that combined ClC-2 KO/CFTR mutant mice survived longer than CFTR mutant mice, associated with an attenuated intestinal phenotype [10]. Ussing chamber experiments using colonic epithelia suggest that ClC-2 function is localized to the basolateral membrane, facilitating Cl reabsorption rather than Cl secretion. Ussing chamber studies using ClC-2 KO mice also demonstrate that basolateral epithelial ClC-2 has a major function promoting NaCl and fluid absorption, not secretion, in distal colon [11]. Immunohistochemical studies have localized ClC-2 to the basolateral membranes of distal colonic surface enterocytes [12–15], but not to the apical membranes. Therefore, the proposed property of Lubiprostone as a ClC2 activator, on the basis of available data, seems questionable [16]. The mechanism of Lubiprostone-induced Cl secretion is also controversial. Lubiprostone was originally proposed to increase the open probability of ClC-2 directly, independently of CFTR function [4]. Lubiprostone, however, activated PG E type (EP) receptors, especially EP4 Y. Akiba J. D. Kaunitz Greater Los Angles Veterans Affairs Healthcare System, Los Angeles, CA, USA
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May the Truth Be with You: Lubiprostone as EP Receptor Agonist/ClC-2 Internalizing “Inhibitor”
Digestive Diseases and Sciences, 2012Co-Authors: Yasutada Akiba, Jonathan D. KaunitzAbstract:Chronic constipation is a common clinical problem. Lubiprostone, a bicyclic fatty acid derived from prostaglandin (PG) E1, has been clinically used for the treatment of chronic constipation in adults. Camilleri et al. [1] first reported that Lubiprostone inhibited gastric emptying, but accelerated small and large intestinal transit, which is associated with postprandial fullness. Subsequently, on the basis of clinical trials, investigators have reported a beneficial effect of Lubiprostone in subjects with chronic constipation and functional bowel disease [2, 3]. Lubiprostone was marketed as belonging to a new therapeutic class, working by a mechanism described as a ClC-2 chloride channel activator. Cuppoletti et al. [4] first reported that Lubiprostone increased Cl secretion by activation of the intestinal epithelial cell ClC-2 channel, localized on the apical membrane of enterocytes. Since epithelial Cl secretion is mainly mediated by the cystic fibrosis transmembrane conductance regulator (CFTR) [5], mutations of which cause the disease cystic fibrosis (CF), enhancement of CFTR-independent Cl secretion has been explored as a rescue treatment for CF. Mice with the CFTR mutation DF508, the most common mutation observed in CF patients [6], and CFTR knockout (KO) exhibit an intestinal phenotype, i.e., intestinal obstruction due to loss of Cl secretion, enhancing their utility as models of CF [7]. Nevertheless, the cellular localization and functional roles of epithelial ClC-2 channel and the mechanism of Lubiprostone effects on Cl secretion have been questioned. First described in 1992 [8], ClC-2 channels are expressed in the stomach, intestine, colon, brain, heart, and muscles. ClC-2 was first proposed to provide a pathway for epithelial Cl secretion, in addition to CFTR [9]. This hypothesis, however, is not supported by the observation that combined ClC-2 KO/CFTR mutant mice survived longer than CFTR mutant mice, associated with an attenuated intestinal phenotype [10]. Ussing chamber experiments using colonic epithelia suggest that ClC-2 function is localized to the basolateral membrane, facilitating Cl reabsorption rather than Cl secretion. Ussing chamber studies using ClC-2 KO mice also demonstrate that basolateral epithelial ClC-2 has a major function promoting NaCl and fluid absorption, not secretion, in distal colon [11]. Immunohistochemical studies have localized ClC-2 to the basolateral membranes of distal colonic surface enterocytes [12–15], but not to the apical membranes. Therefore, the proposed property of Lubiprostone as a ClC2 activator, on the basis of available data, seems questionable [16]. The mechanism of Lubiprostone-induced Cl secretion is also controversial. Lubiprostone was originally proposed to increase the open probability of ClC-2 directly, independently of CFTR function [4]. Lubiprostone, however, activated PG E type (EP) receptors, especially EP4 Y. Akiba J. D. Kaunitz Greater Los Angles Veterans Affairs Healthcare System, Los Angeles, CA, USA
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Lubiprostone Stimulates Duodenal Bicarbonate Secretion in Rats
Digestive Diseases and Sciences, 2009Co-Authors: Misa Mizumori, Yasutada Akiba, Jonathan D. KaunitzAbstract:Background Lubiprostone, a bicyclic fatty acid, is used for the treatment of chronic constipation. No published study has addressed the effect of Lubiprostone on intestinal ion secretion in vivo. Aim The aim of this study was to test the hypothesis that Lubiprostone augments duodenal HCO_3 ^− secretion (DBS). Methods Rat proximal duodenal loops were perfused with pH 7.0 Krebs, control vehicle (medium-chain triglycerides), or Lubiprostone (0.1–10 μM). We measured DBS with flow-through pH and CO_2 electrodes, perfusate [Cl^−] with a Cl^− electrode, and water flux using a non-absorbable ferrocyanide marker. Some rats were pretreated with a potent, selective CFTR antagonist, CFTR_inh-172 (1 mg/kg, ip), 1 h before experiments. Results Perfusion of Lubiprostone concentration dependently increased DBS, whereas net Cl^− output and net water output were only increased at 0.1 μM, compared with vehicle. CFTR_inh-172 reduced Lubiprostone (10 μM)-induced DBS increase, whereas net Cl^− output was also unchanged. Nevertheless, CFTR_inh-172 reduced basal net water output, which was reversed by Lubiprostone. Furthermore, Lubiprostone-induced DBS was inhibited by EP4 receptor antagonist, not by an EP1/2 receptor antagonist or by indomethacin pretreatment. Conclusions In this first study of the effect of Lubiprostone on intestinal ion secretion in vivo, Lubiprostone stimulated CFTR-dependent DBS without changing net Cl^− secretion. This effect supports the hypothesis that Cl^− secreted by CFTR is recycled across the apical membrane by anion exchangers. Recovery of water output during CFTR inhibition suggests that Lubiprostone may improve the intestinal phenotype in CF patients. Furthermore, increased DBS suggests that Lubiprostone may protect the duodenum from acid-induced injury via EP4 receptor activation.
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Lubiprostone stimulates duodenal bicarbonate secretion in rats
Digestive Diseases and Sciences, 2009Co-Authors: Misa Mizumori, Yasutada Akiba, Jonathan D. KaunitzAbstract:Background Lubiprostone, a bicyclic fatty acid, is used for the treatment of chronic constipation. No published study has addressed the effect of Lubiprostone on intestinal ion secretion in vivo.
Douglas A. Drossman - One of the best experts on this subject based on the ideXlab platform.
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analysis of nausea in clinical studies of Lubiprostone for the treatment of constipation disorders
Digestive Diseases and Sciences, 2017Co-Authors: Byron L Cryer, Douglas A. Drossman, William D Chey, Lynn R Webster, Sepideh Habibi, Martin WangAbstract:Lubiprostone is a ClC-2 chloride channel activator approved for the treatment of chronic idiopathic constipation (CIC) and opioid-induced constipation (OIC) in adults and irritable bowel syndrome with constipation (IBS-C) in women. Lubiprostone is generally well tolerated, with nausea being the most common adverse event. To characterize nausea with Lubiprostone using pooled results from clinical studies in patients with CIC, OIC, or IBS-C. Data from three 3- and 4-week placebo-controlled studies and three long-term open-label studies were pooled for the CIC analysis. The OIC and IBS-C analyses each used pooled data from three 12-week placebo-controlled studies and one 36-week open-label extension study. The populations included the following numbers of patients: CIC, 316 (placebo) and 1113 (Lubiprostone 24 mcg twice daily [BID]); OIC, 652 (placebo) and 889 (Lubiprostone 24 mcg BID); and IBS-C, 435 (placebo) and 1011 (Lubiprostone 8 mcg BID). The incidence of nausea in Lubiprostone-treated patients ranged from 11.4 to 31.1%, with the highest incidence in patients with CIC. Among patients with any nausea, most reported only mild or moderate severity (96.5–99.1% across indications) and only one event (83.6–88.7%); most events occurred within the first 5 days of treatment. Nausea was the most common adverse event following the treatment with Lubiprostone. Event rates varied by indication and dose, and the majority of nausea adverse events were mild to moderate in severity. Nausea events predominantly occurred early in the treatment period in all of the pooled study populations.
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Efficacy and Safety of Lubiprostone in Patients with Opioid-Induced Constipation: Phase 3 Study Results and Pooled Analysis of the Effect of Concomitant Methadone Use on Clinical Outcomes
Pain Medicine, 2017Co-Authors: Egilius L.h. Spierings, Douglas A. Drossman, Byron L Cryer, M. Mazen Jamal, Taryn Losch-beridon, Shadreck M. Mareya, Martin WangAbstract:The efficacy and safety of oral Lubiprostone for relieving symptoms of opioid-induced constipation (OIC) in patients with chronic noncancer pain were evaluated in a randomized, double-blind, placebo-controlled study. These data were also pooled with those from two similar phase 3 studies to explore the effects of methadone on treatment response. In the primary study, adults with OIC (fewer than three spontaneous bowel movements [SBMs] per week) were randomized to receive Lubiprostone 24 mcg or placebo twice daily for 12 weeks. The primary end point was a change from baseline in the frequency of SBMs at week 8 in patients without a prior dose reduction. For the pooled analysis, the efficacy of Lubiprostone was compared with placebo in patients receiving methadone or nonmethadone opioids. Responders were defined as patients with nine or more weeks of nonmissing SBM data who had one or more additional SBMs per week from baseline for each week that data were available and three or more SBMs per week for nine or more weeks. In the primary study, the change from baseline at week 8 in SBM frequency was similar in the Lubiprostone and placebo groups (P = 0.842). In the pooled analysis, the response rate was significantly higher with Lubiprostone treatment vs placebo for patients receiving nonmethadone opioids (P = 0.002) but was similar between Lubiprostone treatment and placebo in patients receiving methadone (P = 0.692). The safety profile of Lubiprostone was unaffected by methadone use. The phase 3 study did not meet its primary efficacy end point. However, analysis of pooled data from all phase 3 studies in the OIC clinical development program, stratified by methadone opioid usage, confirmed that Lubiprostone is effective for treatment of OIC in patients taking nonmethadone opioids; no safety concerns were identified based on the type of opioid used.
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effects of baseline abdominal pain and bloating on response to Lubiprostone in patients with irritable bowel syndrome with constipation
Alimentary Pharmacology & Therapeutics, 2016Co-Authors: Lin Chang, Douglas A. Drossman, William D Chey, Martin Wang, Taryn Loschberidon, Peter Lichtlen, Shadreck M. MareyaAbstract:SummaryBackground Lubiprostone (8 μg b.d.) received US Food and Drug Administration (FDA) approval in 2008 for the treatment of constipation-predominant irritable bowel syndrome (IBS-C) in women aged ≥18 years. In 2012, the FDA issued new guidance for IBS-C clinical trials, recommending a composite endpoint incorporating both abdominal pain and stool frequency. Aims In a post hoc analysis, similar criteria were applied to data from two pivotal, phase 3, double-blind, randomised trials of Lubiprostone in patients with IBS-C. Methods Included patients had a baseline spontaneous bowel movement (SBM) frequency <3/week and abdominal pain or bloating ratings ≥1.36 on a 5-point scale [0 (absent) to 4 (very severe)]. Responders (composite endpoint) had a mean pain reduction ≥30% compared with baseline, and an increase from baseline of ≥1 SBM/week for ≥6 of the 12 treatment weeks. Lubiprostone effects on abdominal pain alone were also evaluated, as were bloating alone and in a composite endpoint with stool frequency. Results In pooled data, 325 patients received Lubiprostone and 180 received placebo. Rates of response were higher with Lubiprostone vs. placebo for the composite endpoint of improved pain and stool frequency (26.3% vs. 15.3%, respectively; P = 0.008) and the composite endpoint of improved bloating and stool frequency (23.8% vs. 12.6%, respectively; P = 0.012). Response rates were also higher with Lubiprostone vs. placebo for abdominal pain alone (P = 0.005) and bloating alone (P = 0.012). Conclusions Lubiprostone was significantly more effective than placebo in improving abdominal pain or bloating, and also in composite endpoints that included stool frequency.
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Effects of baseline abdominal pain and bloating on response to Lubiprostone in patients with irritable bowel syndrome with constipation
Alimentary Pharmacology & Therapeutics, 2016Co-Authors: Lin Chang, Douglas A. Drossman, William D Chey, Martin Wang, Taryn Losch-beridon, Peter Lichtlen, Shadreck M. MareyaAbstract:SummaryBackground Lubiprostone (8 μg b.d.) received US Food and Drug Administration (FDA) approval in 2008 for the treatment of constipation-predominant irritable bowel syndrome (IBS-C) in women aged ≥18 years. In 2012, the FDA issued new guidance for IBS-C clinical trials, recommending a composite endpoint incorporating both abdominal pain and stool frequency. Aims In a post hoc analysis, similar criteria were applied to data from two pivotal, phase 3, double-blind, randomised trials of Lubiprostone in patients with IBS-C. Methods Included patients had a baseline spontaneous bowel movement (SBM) frequency
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safety and patient outcomes with Lubiprostone for up to 52 weeks in patients with irritable bowel syndrome with constipation
Alimentary Pharmacology & Therapeutics, 2012Co-Authors: William D Chey, R Panas, Douglas A. Drossman, J F Johanson, Charles Scott, Ryuji UenoAbstract:Summary Background Irritable bowel syndrome with constipation (IBS-C) significantly decreases quality of life and the ability to perform daily living activities. Aim To demonstrate the long-term safety, tolerability and patient outcomes of Lubiprostone in patients with IBS-C. Methods This extension study enrolled 522 IBS-C patients who had completed one of two randomised phase 3 studies. All enrolled patients received open-label Lubiprostone orally for 36-weeks (8 mcg, twice daily). The primary objective was the assessment of long-term safety and tolerability, monitored via adverse events (AEs), laboratory parameters and vital signs. Additional outcome endpoints included monthly responder rates and patient evaluations of IBS-C symptom severity and impact on quality of life. Results The evaluable safety population comprised of 520 patients; 476 of which had patient reported outcome data available. The overall safety profile of Lubiprostone during this study was similar to that observed in the preceding phase 3 studies. The most common AEs were diarrhoea (11.0%), nausea (11.0%), urinary tract infection (9.0%), sinusitis (9.0%) and abdominal distention (5.8%). Diarrhoea and nausea were the most common treatment-related AEs. No serious AEs were considered treatment-related. Seventeen patients discontinued due to a treatment-related AE, of which diarrhoea and nausea accounted for six (1.2%) and three (0.6%) respectively. For responder rates and patient-evaluated parameters (n = 476), all groups experienced significant improvements from baseline, with initial improvements maintained throughout the study. Conclusion In patients with irritable bowel syndrome with constipation, Lubiprostone 8 mcg twice daily was found to be safe and well tolerated over 9–13 months of treatment.
William D Chey - One of the best experts on this subject based on the ideXlab platform.
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analysis of nausea in clinical studies of Lubiprostone for the treatment of constipation disorders
Digestive Diseases and Sciences, 2017Co-Authors: Byron L Cryer, Douglas A. Drossman, William D Chey, Lynn R Webster, Sepideh Habibi, Martin WangAbstract:Lubiprostone is a ClC-2 chloride channel activator approved for the treatment of chronic idiopathic constipation (CIC) and opioid-induced constipation (OIC) in adults and irritable bowel syndrome with constipation (IBS-C) in women. Lubiprostone is generally well tolerated, with nausea being the most common adverse event. To characterize nausea with Lubiprostone using pooled results from clinical studies in patients with CIC, OIC, or IBS-C. Data from three 3- and 4-week placebo-controlled studies and three long-term open-label studies were pooled for the CIC analysis. The OIC and IBS-C analyses each used pooled data from three 12-week placebo-controlled studies and one 36-week open-label extension study. The populations included the following numbers of patients: CIC, 316 (placebo) and 1113 (Lubiprostone 24 mcg twice daily [BID]); OIC, 652 (placebo) and 889 (Lubiprostone 24 mcg BID); and IBS-C, 435 (placebo) and 1011 (Lubiprostone 8 mcg BID). The incidence of nausea in Lubiprostone-treated patients ranged from 11.4 to 31.1%, with the highest incidence in patients with CIC. Among patients with any nausea, most reported only mild or moderate severity (96.5–99.1% across indications) and only one event (83.6–88.7%); most events occurred within the first 5 days of treatment. Nausea was the most common adverse event following the treatment with Lubiprostone. Event rates varied by indication and dose, and the majority of nausea adverse events were mild to moderate in severity. Nausea events predominantly occurred early in the treatment period in all of the pooled study populations.
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effects of baseline abdominal pain and bloating on response to Lubiprostone in patients with irritable bowel syndrome with constipation
Alimentary Pharmacology & Therapeutics, 2016Co-Authors: Lin Chang, Douglas A. Drossman, William D Chey, Martin Wang, Taryn Loschberidon, Peter Lichtlen, Shadreck M. MareyaAbstract:SummaryBackground Lubiprostone (8 μg b.d.) received US Food and Drug Administration (FDA) approval in 2008 for the treatment of constipation-predominant irritable bowel syndrome (IBS-C) in women aged ≥18 years. In 2012, the FDA issued new guidance for IBS-C clinical trials, recommending a composite endpoint incorporating both abdominal pain and stool frequency. Aims In a post hoc analysis, similar criteria were applied to data from two pivotal, phase 3, double-blind, randomised trials of Lubiprostone in patients with IBS-C. Methods Included patients had a baseline spontaneous bowel movement (SBM) frequency <3/week and abdominal pain or bloating ratings ≥1.36 on a 5-point scale [0 (absent) to 4 (very severe)]. Responders (composite endpoint) had a mean pain reduction ≥30% compared with baseline, and an increase from baseline of ≥1 SBM/week for ≥6 of the 12 treatment weeks. Lubiprostone effects on abdominal pain alone were also evaluated, as were bloating alone and in a composite endpoint with stool frequency. Results In pooled data, 325 patients received Lubiprostone and 180 received placebo. Rates of response were higher with Lubiprostone vs. placebo for the composite endpoint of improved pain and stool frequency (26.3% vs. 15.3%, respectively; P = 0.008) and the composite endpoint of improved bloating and stool frequency (23.8% vs. 12.6%, respectively; P = 0.012). Response rates were also higher with Lubiprostone vs. placebo for abdominal pain alone (P = 0.005) and bloating alone (P = 0.012). Conclusions Lubiprostone was significantly more effective than placebo in improving abdominal pain or bloating, and also in composite endpoints that included stool frequency.
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Effects of baseline abdominal pain and bloating on response to Lubiprostone in patients with irritable bowel syndrome with constipation
Alimentary Pharmacology & Therapeutics, 2016Co-Authors: Lin Chang, Douglas A. Drossman, William D Chey, Martin Wang, Taryn Losch-beridon, Peter Lichtlen, Shadreck M. MareyaAbstract:SummaryBackground Lubiprostone (8 μg b.d.) received US Food and Drug Administration (FDA) approval in 2008 for the treatment of constipation-predominant irritable bowel syndrome (IBS-C) in women aged ≥18 years. In 2012, the FDA issued new guidance for IBS-C clinical trials, recommending a composite endpoint incorporating both abdominal pain and stool frequency. Aims In a post hoc analysis, similar criteria were applied to data from two pivotal, phase 3, double-blind, randomised trials of Lubiprostone in patients with IBS-C. Methods Included patients had a baseline spontaneous bowel movement (SBM) frequency
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safety and patient outcomes with Lubiprostone for up to 52 weeks in patients with irritable bowel syndrome with constipation
Alimentary Pharmacology & Therapeutics, 2012Co-Authors: William D Chey, R Panas, Douglas A. Drossman, J F Johanson, Charles Scott, Ryuji UenoAbstract:Summary Background Irritable bowel syndrome with constipation (IBS-C) significantly decreases quality of life and the ability to perform daily living activities. Aim To demonstrate the long-term safety, tolerability and patient outcomes of Lubiprostone in patients with IBS-C. Methods This extension study enrolled 522 IBS-C patients who had completed one of two randomised phase 3 studies. All enrolled patients received open-label Lubiprostone orally for 36-weeks (8 mcg, twice daily). The primary objective was the assessment of long-term safety and tolerability, monitored via adverse events (AEs), laboratory parameters and vital signs. Additional outcome endpoints included monthly responder rates and patient evaluations of IBS-C symptom severity and impact on quality of life. Results The evaluable safety population comprised of 520 patients; 476 of which had patient reported outcome data available. The overall safety profile of Lubiprostone during this study was similar to that observed in the preceding phase 3 studies. The most common AEs were diarrhoea (11.0%), nausea (11.0%), urinary tract infection (9.0%), sinusitis (9.0%) and abdominal distention (5.8%). Diarrhoea and nausea were the most common treatment-related AEs. No serious AEs were considered treatment-related. Seventeen patients discontinued due to a treatment-related AE, of which diarrhoea and nausea accounted for six (1.2%) and three (0.6%) respectively. For responder rates and patient-evaluated parameters (n = 476), all groups experienced significant improvements from baseline, with initial improvements maintained throughout the study. Conclusion In patients with irritable bowel syndrome with constipation, Lubiprostone 8 mcg twice daily was found to be safe and well tolerated over 9–13 months of treatment.
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clinical trial Lubiprostone in patients with constipation associated irritable bowel syndrome results of two randomized placebo controlled studies
Alimentary Pharmacology & Therapeutics, 2009Co-Authors: Douglas A. Drossman, R Panas, William D Chey, J F Johanson, Ronnie Fass, Charles Scott, Ryuji UenoAbstract:Summary Background Effective treatments for irritable bowel syndrome with constipation (IBS-C) are lacking. Aim To assess the efficacy and safety of Lubiprostone in IBS-C. Methods A combined analysis was performed among 1171 patients with a Rome II diagnosis of IBS-C in two phase-3 randomized trials of Lubiprostone 8 mcg vs. placebo twice daily for 12 weeks. Using a balanced seven-point Likert scale ranging from significantly relieved (+3), to significantly worse (−3), patients responded on their electronic diary to the question: ‘How would you rate your relief of IBS symptoms over the past week compared to how you felt before you entered the study?’. The primary efficacy endpoint was the percentage of overall responders. Results Using an intent-to-treat analysis with last observation carried forward, a significantly higher percentage of Lubiprostone-treated patients were considered overall responders compared with those treated with placebo (17.9% vs. 10.1%, P = 0.001). Patients treated with Lubiprostone reported a similar incidence of adverse events to those treated with placebo. Conclusions The percentage of overall responders based on patient-rated assessments of IBS-C symptoms was significantly improved in patients treated with Lubiprostone 8 mcg twice daily compared to those treated with placebo. Lubiprostone was well tolerated with a favourable safety profile.
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efficacy of Lubiprostone for the treatment of opioid induced constipation analyzed by opioid class
Pain Medicine, 2018Co-Authors: Lynn R Webster, Shadreck M. Mareya, Taryn Loschberidon, Peter Lichtlen, Randall P Brewer, Martin WangAbstract:Objectives:To examine the efficacy and safety of Lubiprostone for the treatment of opioid-induced constipation (OIC) in patients by opioid class received. Design:Data were pooled from three phase III, randomized, double-blind, placebo-controlled studies. Subjects/Setting:Adults with chronic noncancer pain receiving opioid therapy for 30 or more days and diagnosed with OIC. Methods:Overall mean change from baseline in spontaneous bowel movement (SBM) frequency, overall treatment response (≥1 SBM/week improvement over baseline SBM frequency in all treatment weeks with available data and ≥3 SBMs/week for ≥9 of the 12 weeks of treatment), and OIC-related symptoms were examined in patients taking opioids. Data were pooled and analyzed by opioid group. Results:In patients receiving phenanthrene opioids (e.g., oxycodone; N = 1,159), Lubiprostone significantly increased overall mean changes in SBM frequency from baseline (P = 0.0001), increased overall response rate (P = 0.0024), and improved OIC symptoms (P ≤ 0.0229) vs placebo. Patients receiving phenylpiperidine opioids (e.g., fentanyl; N = 137) had significant improvement in SBM frequency (P = 0.0129) and favorable trends in response rates (21.4% vs 9.8%; P = 0.0723) and OIC symptoms vs placebo. Efficacy was not observed in overall analyses of patients receiving diphenylheptane opioids (e.g., methadone), although an increase in SBM frequency was observed in patients who received a morphine-equivalent daily dose of 200 or fewer mg, suggesting a dose-dependent negative interference of this opioid class on Lubiprostone effects. For all groups, the Lubiprostone adverse event profile was similar; the most common treatment-emergent adverse events were nausea and diarrhea. Conclusions:In patients using commonly prescribed opioids, Lubiprostone is effective and generally well tolerated for the treatment of OIC.
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Efficacy and Safety of Lubiprostone in Patients with Opioid-Induced Constipation: Phase 3 Study Results and Pooled Analysis of the Effect of Concomitant Methadone Use on Clinical Outcomes
Pain Medicine, 2017Co-Authors: Egilius L.h. Spierings, Douglas A. Drossman, Byron L Cryer, M. Mazen Jamal, Taryn Losch-beridon, Shadreck M. Mareya, Martin WangAbstract:The efficacy and safety of oral Lubiprostone for relieving symptoms of opioid-induced constipation (OIC) in patients with chronic noncancer pain were evaluated in a randomized, double-blind, placebo-controlled study. These data were also pooled with those from two similar phase 3 studies to explore the effects of methadone on treatment response. In the primary study, adults with OIC (fewer than three spontaneous bowel movements [SBMs] per week) were randomized to receive Lubiprostone 24 mcg or placebo twice daily for 12 weeks. The primary end point was a change from baseline in the frequency of SBMs at week 8 in patients without a prior dose reduction. For the pooled analysis, the efficacy of Lubiprostone was compared with placebo in patients receiving methadone or nonmethadone opioids. Responders were defined as patients with nine or more weeks of nonmissing SBM data who had one or more additional SBMs per week from baseline for each week that data were available and three or more SBMs per week for nine or more weeks. In the primary study, the change from baseline at week 8 in SBM frequency was similar in the Lubiprostone and placebo groups (P = 0.842). In the pooled analysis, the response rate was significantly higher with Lubiprostone treatment vs placebo for patients receiving nonmethadone opioids (P = 0.002) but was similar between Lubiprostone treatment and placebo in patients receiving methadone (P = 0.692). The safety profile of Lubiprostone was unaffected by methadone use. The phase 3 study did not meet its primary efficacy end point. However, analysis of pooled data from all phase 3 studies in the OIC clinical development program, stratified by methadone opioid usage, confirmed that Lubiprostone is effective for treatment of OIC in patients taking nonmethadone opioids; no safety concerns were identified based on the type of opioid used.
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Lubiprostone for opioid induced constipation does not interfere with opioid analgesia in patients with chronic noncancer pain
Pain Practice, 2017Co-Authors: Egilius L.h. Spierings, Taryn Loschberidon, Randall P Brewer, Richard Rauck, Shadreck M. MareyaAbstract:Objective To determine whether Lubiprostone 24 μg twice daily (BID), administered to relieve opioid-induced constipation (OIC), affects opioid analgesia in patients with chronic noncancer pain. Methods Data were pooled from 3 randomized, double-blind, placebo-controlled trials of Lubiprostone in adults with chronic noncancer pain receiving stable opioid analgesia and who had documented OIC. In each study, Lubiprostone 24 μg BID or placebo was administered for 12 weeks for relief of OIC using a common protocol. The Brief Pain Inventory short form (BPI-SF) was administered, and opioid use (expressed as morphine-equivalent daily dose [MEDD]) was recorded at baseline and months 1, 2, and 3. The BPI-SF provided patient scores for pain severity, the worst pain experienced in the past 24 hours, and pain interference with daily life. Results The pooled patient population (N = 1300) was predominately female (62.5%) and white (82.1%), with a mean age of 50.5 years. The MEDD was 97.5 mg (range, 5 to 3656 mg) in patients receiving placebo and 112.5 mg (range, 4 to 7605 mg) in patients treated with Lubiprostone. Lubiprostone 24 μg BID treatment did not appear to affect opioid use or pain scores; changes from baseline were not significantly different with placebo vs. Lubiprostone 24 μg BID at months 1, 2, and 3 for MEDD (P ≥ 0.435) and for BPI-SF scores for pain interference, pain severity, and worst pain (P ≥ 0.402). Discussion Lubiprostone 24 μg BID administered for relief of OIC in patients with chronic noncancer pain does not interfere with opioid analgesia.
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effects of baseline abdominal pain and bloating on response to Lubiprostone in patients with irritable bowel syndrome with constipation
Alimentary Pharmacology & Therapeutics, 2016Co-Authors: Lin Chang, Douglas A. Drossman, William D Chey, Martin Wang, Taryn Loschberidon, Peter Lichtlen, Shadreck M. MareyaAbstract:SummaryBackground Lubiprostone (8 μg b.d.) received US Food and Drug Administration (FDA) approval in 2008 for the treatment of constipation-predominant irritable bowel syndrome (IBS-C) in women aged ≥18 years. In 2012, the FDA issued new guidance for IBS-C clinical trials, recommending a composite endpoint incorporating both abdominal pain and stool frequency. Aims In a post hoc analysis, similar criteria were applied to data from two pivotal, phase 3, double-blind, randomised trials of Lubiprostone in patients with IBS-C. Methods Included patients had a baseline spontaneous bowel movement (SBM) frequency <3/week and abdominal pain or bloating ratings ≥1.36 on a 5-point scale [0 (absent) to 4 (very severe)]. Responders (composite endpoint) had a mean pain reduction ≥30% compared with baseline, and an increase from baseline of ≥1 SBM/week for ≥6 of the 12 treatment weeks. Lubiprostone effects on abdominal pain alone were also evaluated, as were bloating alone and in a composite endpoint with stool frequency. Results In pooled data, 325 patients received Lubiprostone and 180 received placebo. Rates of response were higher with Lubiprostone vs. placebo for the composite endpoint of improved pain and stool frequency (26.3% vs. 15.3%, respectively; P = 0.008) and the composite endpoint of improved bloating and stool frequency (23.8% vs. 12.6%, respectively; P = 0.012). Response rates were also higher with Lubiprostone vs. placebo for abdominal pain alone (P = 0.005) and bloating alone (P = 0.012). Conclusions Lubiprostone was significantly more effective than placebo in improving abdominal pain or bloating, and also in composite endpoints that included stool frequency.
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Effects of baseline abdominal pain and bloating on response to Lubiprostone in patients with irritable bowel syndrome with constipation
Alimentary Pharmacology & Therapeutics, 2016Co-Authors: Lin Chang, Douglas A. Drossman, William D Chey, Martin Wang, Taryn Losch-beridon, Peter Lichtlen, Shadreck M. MareyaAbstract:SummaryBackground Lubiprostone (8 μg b.d.) received US Food and Drug Administration (FDA) approval in 2008 for the treatment of constipation-predominant irritable bowel syndrome (IBS-C) in women aged ≥18 years. In 2012, the FDA issued new guidance for IBS-C clinical trials, recommending a composite endpoint incorporating both abdominal pain and stool frequency. Aims In a post hoc analysis, similar criteria were applied to data from two pivotal, phase 3, double-blind, randomised trials of Lubiprostone in patients with IBS-C. Methods Included patients had a baseline spontaneous bowel movement (SBM) frequency
