352 LX1032: A Potential New Therapy for Chronic Diarrhea in Carcinoid Syndrome (CS)

Pappas, S. Chris; Brown, Philip M.; Turnage, Anne; Frazier, Kenneth; Yang, Qi; Shi, Zhi-Cai; Liu, Qingyun

doi:10.1016/s0016-5085(09)60255-9

Cited by 3 publications

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“…Because gastrointestinal transit time and gastric emptying are abnormal in TPH2KO mice,23 the observations are also consistent with the idea that peripheral TPH inhibitors fail to enter the murine myenteric plexus, block TPH2, or affect neuronal stores of 5-HT. LX1032, however, relieves the excessive motility seen in patients with carcinoid syndrome,43 implying that LX1032 reaches the systemic circulation and inhibits 5-HT biosynthesis by metastatic symptom-inducing tumour cells.…”

Section: Discussionmentioning

confidence: 99%

Pharmacological reduction of mucosal but not neuronal serotonin opposes inflammation in mouse intestine

Margolis

Stevanovic

et al. 2013

Gut

165

140

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Objective Enterochromaffin cell-derived serotonin (5-HT) promotes intestinal inflammation. We tested hypotheses that peripheral tryptophan hydroxylase (TPH) inhibitors, administered orally, block 5-HT biosynthesis and deplete 5-HT from enterochromaffin cells sufficiently to ameliorate intestinal inflammation; moreover, peripheral TPH inhibitors fail to enter the murine enteric nervous system (ENS) or central nervous systems and thus do not affect constitutive gastrointestinal motility. Design Two peripheral TPH inhibitors, LP-920540 and telotristat etiprate (LX1032; LX1606) were given orally to mice. Effects were measured on 5-HT levels in the gut, blood and brain, 5-HT immunoreactivity in the ENS, gastrointestinal motility and severity of trinitrobenzene sulfonic acid (TNBS)-induced colitis. Quantitation of clinical scores, histological damage and intestinal expression of inflammation-associated cytokines and chemokines with focused microarrays and real-time reverse transcriptase PCR were employed to evaluate the severity of intestinal inflammation. Results LP-920540 and LX1032 reduced 5-HT significantly in the gut and blood but not in the brain. Neither LP-920540 nor LX1032 decreased 5-HT immunoreactive neurons or fibres in the myenteric plexus and neither altered total gastrointestinal transit time, colonic motility or gastric emptying in mice. In contrast, oral LP-920540 and LX1032 reduced the severity of TNBS-induced colitis; the expression of 24% of 84 genes encoding inflammation-related cytokines and chemokines was lowered at least fourfold and the reduced expression of 17% was statistically significant. Conclusions Observations suggest that that peripheral TPH inhibitors uncouple the positive linkage of enterochromaffin cell-derived 5-HT to intestinal inflammation. Because peripheral TPH inhibitors evidently do not enter the murine ENS, they lack deleterious effects on constitutive intestinal motility in mice.

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Section: Discussionmentioning

confidence: 99%

Pharmacological reduction of mucosal but not neuronal serotonin opposes inflammation in mouse intestine

Margolis

Stevanovic

et al. 2013

Gut

165

140

View full text Add to dashboard Cite

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“…In view of the low systemic exposure of LX‐1031, treatment of carcinoid diarrhea may require development of an analog (LX‐1032) 46 with greater systemic exposure to target synthesis of 5‐HT in metastatic carcinoid tumor cells. Review of LX‐1032 is outside the scope of the current review of LX‐1031.…”

Section: Pharmacologymentioning

confidence: 99%

LX-1031, a tryptophan 5-hydroxylase inhibitor, and its potential in chronic diarrhea associated with increased serotonin

Camilleri¹

2010

Neurogastroenterology &Amp; Motility

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Background LX-1031 is an oral, small-molecule tryptophan 5-hydroxylase (TPH) inhibitor that reduces serotonin (5-HT) synthesis peripherally. It has potential for illnesses characterized by excess 5-HT, such as diarrhea-predominant irritable bowel syndrome (IBS-D) and carcinoid diarrhea. In vitro, inhibition of TPH1 occurred in 10−8 – 10−7 M range. In vivo in rodents, LX-1031 has no effect on brain 5-HT while dose-dependently reducing 5-HT, particularly in the small bowel. Pharmacokinetics After oral LX1031 in humans, systemic exposure is very low, plasma concentrations are linear in dose range 250 mg QD to 750 mg QID; the median T1/2 for elimination is ~20 hrs, and repeat administration for 14 days doubles Cmax. Pharmacodynamics In ascending-single-dose and multiple dose (14 day) trials in healthy volunteers, LX-1031 2g-4g/day significantly reduced urinary 5-hydroxyindoleacetic acid (5-HIAA) starting by day 5, and persisting over the 14 day exposure. Clinical safety and efficacy There are no dose limiting toxicities in healthy subjects or remarkable adverse effects in clinical trials to date. Over a 28-day treatment period, LX-1031 was associated with improved weekly global scores (2/4 weeks) and improved stool consistency with lower urinary 5-HIAA excretion. Conclusion LX-1031 appears promising for chronic diarrhea associated with increased 5-HT expression including IBS-D. Optimal doses, efficacy and safety in IBS clinical trials need to be fully elucidated; low systemic exposure, selectivity for TPH1 over TPH2, and lack of effect on brain 5-HT in several species suggest that LX-1031 is unlikely to cause affective disorders.

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Telotristat Ethyl: First Global Approval

Markham

2017

Drugs

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Telotristat ethyl (Xermelo™) is a peripheral tryptophan hydroxylase (TPH) inhibitor that was developed by Lexicon Pharmaceuticals, Inc. for the treatment of carcinoid syndrome. Many neuroendocrine tumours secrete serotonin (5-HT) into the blood stream, resulting in a number of symptoms, notably diarrhoea. Telotristat ethyl inhibits TPH, thereby reducing the production of 5-HT. In February 2017, telotristat ethyl was approved in the USA for the treatment of carcinoid syndrome diarrhoea in combination with somatostatin analog (SSA) therapy in adults inadequately controlled by SSA therapy. This article summarizes the milestones in the development of telotristat ethyl leading to this first global approval.

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352 LX1032: A Potential New Therapy for Chronic Diarrhea in Carcinoid Syndrome (CS)

Cited by 3 publications

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Pharmacological reduction of mucosal but not neuronal serotonin opposes inflammation in mouse intestine

Pharmacological reduction of mucosal but not neuronal serotonin opposes inflammation in mouse intestine

LX-1031, a tryptophan 5-hydroxylase inhibitor, and its potential in chronic diarrhea associated with increased serotonin

Telotristat Ethyl: First Global Approval

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