Arthur Sands

Lexicon Pharmaceuticals, The Woodlands, Texas, United States

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Publications (51)495.03 Total impact

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    ABSTRACT: The sodium-dependent glucose transporter 2 (SGLT2) inhibitors are an important emerging class for the treatment of diabetes. Development of SGLT2 inhibitors has been oriented around a desire for high selectivity for the SGLT2 protein relative to the SGLT1 protein. More recently, genetic and pharmacology research in mice has indicated that gastrointestinal SGLT1 inhibition may also be an appropriate therapeutic target to treat diabetes. Combining SGLT1 and SGLT2 inhibition in a single molecule would provide complementary insulin-independent mechanisms to treat diabetes. Therefore, sotagliflozin (LX4211) has been developed as a dual inhibitor of SGLT1 and SGLT2. The differentiating clinical features of dual inhibitor of SGLT1 and SGLT2 include a large postprandial glucose reduction, elevation of glucagon-like peptide 1 and modest urinary glucose excretion. These features may have clinical implications for the use of sotagliflozin in the treatment of both type 1 and type 2 diabetes. © The Author(s) 2015.
    Diabetes & Vascular Disease Research 03/2015; 12(2):101-10. DOI:10.1177/1479164114563304 · 3.04 Impact Factor
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    ABSTRACT: Oral agents are needed that improve glycemic control without increasing hypoglycemic events in patients with type 1 diabetes (T1D). Sotagliflozin may meet this need, because this compound lowers blood glucose through the insulin-independent mechanisms of inhibiting kidney SGLT2 and intestinal SGLT1. We examined the effect of sotagliflozin on glycemic control and rate of hypoglycemia measurements in T1D mice maintained on a low daily insulin dose, and compared these results to those from mice maintained in better glycemic control with a higher daily insulin dose alone. Nonobese diabetes-prone mice with cyclophosphamide-induced T1D were randomized to receive one of four daily treatments: 0.2 U insulin/vehicle, 0.05 U insulin/vehicle, 0.05 U insulin/2 mg/kg sotagliflozin or 0.05 U insulin/30 mg/kg sotagliflozin. Insulin was delivered subcutaneously by micro-osmotic pump; the day after pump implantation, mice received their first of 22 once-daily oral doses of sotagliflozin or vehicle. Glycemic control was monitored by measuring fed blood glucose and hemoglobin A1c levels. Blood glucose levels decreased rapidly and comparably in the 0.05 U insulin/sotagliflozin-treated groups and the 0.2 U insulin/vehicle group compared to the 0.05 U insulin/vehicle group, which had significantly higher levels than the other three groups from day 2 through day 23. A1c levels were also significantly higher in the 0.05 U insulin/vehicle group compared to the other three groups on day 23. Importantly, the 0.2 U insulin/vehicle group had, out of 100 blood glucose measurements, 13 that were <70 mg/dL compared to one of 290 for the other three groups combined. Sotagliflozin significantly improved glycemic control, without increasing the rate of hypoglycemia measurements, in diabetic mice maintained on a low insulin dose. This sotagliflozin-mediated improvement in glycemic control was comparable to that achieved by raising the insulin dose alone, but was not accompanied by the increased rate of hypoglycemia measurements observed with the higher insulin dose.
    Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy 02/2015; 8:121-7. DOI:10.2147/DMSO.S76342
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    ABSTRACT: Context: Carcinoid syndrome (CS) is associated with elevated serotonin, diarrhea, flushing and increased risk of valvular heart disease. Many patients respond to somatostatin analogs (SSAs) initially; but response diminishes in most patients. Additional options are needed. Objective: To assess whether telotristat etiprate (TE) can reduce gastrointestinal (GI) symptoms in CS and reduce urinary 5-HIAA (a biomarker of serotonin). Design: Prospective, exploratory, dose-escalating 12-week, open-label, multicenter study of TE with efficacy and safety analyses Setting: Multicenter study Patients: Eligible patients had metastatic, well-differentiated, neuroendocrine tumors and CS with ≥4 bowel movements (BMs)/day. SSA use was allowed. Interventions: Telotristat etiprate, a novel oral inhibitor of peripheral serotonin synthesis. Main Outcome Measures: Primary: Safety. Secondary: Daily BMs, stool form, urinary 5-hydroxyindoleacetic acid (u5-HIAA) Results: Fifteen patients were enrolled and 14 completed the treatment period. All patients experienced reductions in BMs/day (mean decrease 43.5%). A 74.2% mean reduction in u5-HIAA, the main metabolite of serotonin, was observed, with generally greater reductions in patients with greater reductions in BMs/day. Nine (75%) patients reported "adequate relief" of GI symptoms at 12-weeks, compared with 2 (17%) at baseline. Stool form and flushing also improved. AEs were mostly gastrointestinal (n=10, 67%), consistent with underlying illness; 3 AEs were serious (abdominal pain, diarrhea, and gastroenteritis), but judged unrelated. Conclusion: TE was generally safe and well tolerated. Patients experienced substantial improvement in CS and reductions in u5-HIAA, consistent with TE's mechanism of action. These results support further evaluation in Phase 3 studies.
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    ABSTRACT: We sought to assess the efficacy and safety profile of LX4211, a dual inhibitor of sodium-glucose cotransporter1 (SGLT1) and SGLT2, in patients with type 2 diabetes and renal impairment. Thirty-one patients with an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m(2) were randomly assigned to receive 400 mg of LX4211 or placebo for 7 days. The primary end point was the change from baseline to day 7 in postprandial glucose (PPG) levels. Other end points included changes in fasting plasma glucose levels, glucagon-like peptide 1 levels, urinary glucose excretion (UGE), and blood pressure. LX4211 therapy significantly reduced PPG levels relative to placebo in the total population and in patients with an eGFR <45 mL/min/1.73 m(2), with a placebo-adjusted decrease in incremental AUCpredose-4 of 73.5 mg·h/dL (P = 0.009) and 137.2 mg·h/dL (P = 0.001) for the total population and the eGFR <45 mL/min/1.73 m(2) subgroup, respectively. There was a significant reduction in fasting plasma glucose levels relative to baseline of -27.1 mg/dL (P < 0.001). Total and active glucagon-like peptide 1 levels were significantly elevated relative to placebo with LX4211 dosing, and UGE was significantly elevated with placebo-subtracted measures of 38.7, 53.5, and 20.4 g/24 h (P ≤ 0.007 for all 3) in the total population, eGFR 45 to 59 mL/min/1.73 m(2), and eGFR <45 mL/min/1.73 m(2) subgroups, respectively. The PPG effects were maintained in patients with an eGFR <45 mL/min/1.73 m(2) despite the expected reduction in UGE, suggesting that dual SGLT1 and SGLT2 inhibition with LX4211 could prove useful for the treatment of patients with type 2 diabetes and renal impairment. ClinicalTrials.gov identifier: NCT01555008. Copyright © 2014 Elsevier HS Journals, Inc. All rights reserved.
    Clinical Therapeutics 12/2014; 37(1). DOI:10.1016/j.clinthera.2014.10.026 · 2.59 Impact Factor
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    ABSTRACT: Screening gene function in vivo is a powerful approach to discover novel drug targets. We present high-throughput screening (HTS) data for 3 762 distinct global gene knockout (KO) mouse lines with viable adult homozygous mice generated using either gene-trap or homologous recombination technologies. Bone mass was determined from DEXA scans of male and female mice at 14 weeks of age and by microCT analyses of bones from male mice at 16 weeks of age. Wild-type (WT) cagemates/littermates were examined for each gene KO. Lethality was observed in an additional 850 KO lines. Since primary HTS are susceptible to false positive findings, additional cohorts of mice from KO lines with intriguing HTS bone data were examined. Aging, ovariectomy, histomorphometry and bone strength studies were performed and possible non-skeletal phenotypes were explored. Together, these screens identified multiple genes affecting bone mass: 23 previously reported genes (Calcr, Cebpb, Crtap, Dcstamp, Dkk1, Duoxa2, Enpp1, Fgf23, Kiss1/Kiss1r, Kl (Klotho), Lrp5, Mstn, Neo1, Npr2, Ostm1, Postn, Sfrp4, Slc30a5, Slc39a13, Sost, Sumf1, Src, Wnt10b), five novel genes extensively characterized (Cldn18, Fam20c, Lrrk1, Sgpl1, Wnt16), five novel genes with preliminary characterization (Agpat2, Rassf5, Slc10a7, Slc26a7, Slc30a10) and three novel undisclosed genes coding for potential osteoporosis drug targets.
    10/2014; DOI:10.1038/boneres.2014.34
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    ABSTRACT: To assess the dose-ranging efficacy and safety of LX4211, a dual inhibitor of sodium glucose cotransporter 1 (SGLT1) and SGLT2, in type 2 diabetes.
    Diabetes Care 09/2014; DOI:10.2337/dc14-0890 · 8.57 Impact Factor
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    ABSTRACT: Serotonin produced by neuroendocrine tumors is believed to be a principal cause of the diarrhea in carcinoid syndrome. We assessed the safety and efficacy of telotristat etiprate, an oral serotonin synthesis inhibitor, in patients with diarrhea associated with carcinoid syndrome. In this prospective, randomized study, patients with evidence of carcinoid tumor and ≥4 bowel movements (BMs)/day despite stable-dose octreotide LAR depot therapy were enrolled in sequential, escalating, cohorts of 4 patients/cohort. In each cohort, 1 patient was randomly assigned to placebo and 3 patients to telotristat etiprate, at 150, 250, 350, or 500 mg 3x/day (tid). In a subsequent cohort, 1 patient was assigned to placebo and 6 patients to telotristat etiprate 500 mg tid. Patients were assessed for safety, BM frequency (daily diary), 24-hour urinary 5-hydroxyindoleacetic acid (u5-HIAA), and adequate relief of carcinoid gastrointestinal symptoms (using a weekly questionnaire). Twenty-three patients were treated; 18 received telotristat etiprate and 5 received placebo. Adverse events were generally mild. Among evaluable telotristat etiprate-treated patients, 5/18 (28%) experienced a >30% reduction in BM frequency for >2 weeks, 9/16 (56%) experienced biochemical response (>50% reduction or normalization in 24-hour u5-HIAA) at Week 2 or 4, and 10/18 (56%) reported adequate relief during at least 1 of the first 4 weeks of treatment. Similar activity was not observed in placebo-treated patients. Telotristat etiprate was well tolerated. Our observations suggest that telotristat etiprate has activity in controlling diarrhea associated with carcinoid syndrome. Further studies confirming these findings are warranted.
    Endocrine Related Cancer 07/2014; DOI:10.1530/ERC-14-0173 · 4.91 Impact Factor
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    ABSTRACT: LX4211 is a first-in-class dual inhibitor of sodium-dependent glucose cotransporters 1 and 2 (SGLT1 and SGLT2). SGLT1 is the primary transporter for glucose absorption from the gastrointestinal tract, and SGLT2 is the primary transporter for glucose reabsorption in the kidney. SGLT1 inhibition reduces postprandial glucose (PPG) levels and increases the release of gastrointestinal peptides such as glucagon-like peptide 1 (GLP-1) and peptide tyrosine tyrosine (PYY), whereas SGLT2 inhibition results in increased urinary glucose excretion (UGE). This study evaluated how timing of dose relative to meals changes the pharmacodynamic (PD) effects of LX4211 treatment, including effects on UGE, fasting plasma glucose, PPG, insulin, total and active GLP-1, and PYY. The safety and tolerability of LX4211 in healthy subjects were also assessed. This was a randomized, double-blind, placebo-controlled, multiple-dose study to determine the PD effects of LX4211 dose timing relative to meals in 12 healthy subjects. Blood and urine were collected for the analysis of PD variables. Twelve healthy subjects 30 to 51 years of age were enrolled and treated. Treatment with LX4211 resulted in significant elevation of total and active GLP-1, and PYY while significantly decreasing PPG levels relative to placebo, likely by reducing SGLT1-mediated intestinal glucose absorption. Comparisons performed among the dosing schedules indicated that dosing immediately before breakfast maximized the PD effects of LX4211 on both SGLT1 and SGLT2 inhibition. The comparative results suggested distinct SGLT1 effects on GLP-1, PYY, glucose, and insulin, which were separate from SGLT2-mediated effects, indicating that SGLT1 inhibition with LX4211 may be clinically meaningful. All treatments were well tolerated with no evidence of diarrhea with LX4211 treatment. This clinical study indicates that dosing of LX4211 immediately before breakfast maximized the PD effects of both SGLT1 and SGLT 2 inhibition and provided a convenient dosing schedule for future trials. LX4211 was safe and well tolerated and, due to its SGLT1 inhibition, produced strong PPG reductions and low UGE relative to selective SGLT2 inhibitors. LX4211 may provide a promising new therapy for patients with type 2 diabetes mellitus. The potential long-term clinical benefits and safety of LX4211 treatment will need to be confirmed in large clinical trials. ClinicalTrials.gov identifier: NCT01334242.
    Clinical Therapeutics 07/2013; DOI:10.1016/j.clinthera.2013.06.011 · 2.59 Impact Factor
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    ABSTRACT: Sodium-glucose cotransporters 1 (SGLT1) and 2 (SGLT2) are the major cellular transporters responsible for gastrointestinal (GI) glucose absorption and renal glucose reabsorption, respectively. LX4211, a dual inhibitor of SGLT1 and SGLT2, reduces glucose absorption from the GI tract and enhances urinary glucose excretion. Although several SGLT2-selective inhibitors have been tested in large phase 2 studies, dual inhibition of SGLT1 and SGLT2 is novel at this stage of drug development, and it has implications for clinical-trial design. In this article, we describe the design and rationale of a phase 2, multicenter, randomized, double-blind, placebo-controlled, parallel group study to evaluate the safety and efficacy of LX4211 in subjects with type 2 diabetes mellitus who have inadequate glycemic control on metformin monotherapy. The primary endpoint is the change in glycated hemoglobin A1c from baseline to week 12. Secondary endpoints include the proportion of subjects achieving a glycated hemoglobin A1c value of <7%, change from baseline in fasting plasma glucose and postprandial glucose (as part of an oral glucose tolerance test), body weight, and blood pressure. Safety is evaluated with particular focus on hypoglycemia, GI symptoms, and incidence of genitourinary tract infections.
    Clinical Cardiology 07/2013; 36(7). DOI:10.1002/clc.22125 · 2.23 Impact Factor
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    ABSTRACT: LX4211, a dual sodium/glucose cotransporter 1 (SGLT1) and SGLT2 inhibitor, is thought to decrease both renal glucose reabsorption by inhibiting SGLT2 and intestinal glucose absorption by inhibiting SGLT1. In clinical trials in patients with type 2 diabetes mellitus (T2DM), LX4211 treatment improved glycemic control while increasing circulating levels of glucagon-like peptide (GLP)-1 and peptide YY (PYY). To better understand how LX4211 increases GLP-1 and PYY levels, we challenged SGLT1 knockout (-/-) mice, SGLT2 -/- mice, and LX4211-treated mice with oral glucose. LX4211-treated mice and SGLT1 -/- mice had increased levels of plasma GLP-1, plasma PYY and intestinal glucose during the 6 hours after a glucose-containing meal, as reflected by area-under-the-curve (AUC) values, whereas SGLT2 -/- mice showed no response. LX4211-treated mice and SGLT1 -/- mice also had increased GLP-1 AUC, decreased glucose-dependent insulinotropic polypeptide (GIP) AUC, and decreased blood glucose excursions during the 6 hours after a challenge with oral glucose alone. However, GLP-1 and GIP levels were not increased in LX4211-treated mice, and were decreased in SGLT1 -/- mice, 5 minutes after oral glucose, consistent with studies linking decreased intestinal SGLT1 activity with reduced GLP-1 and GIP levels five minutes after oral glucose. These data suggest LX4211 reduces intestinal glucose absorption by inhibiting SGLT1, resulting in net increases in GLP-1 and PYY release and decreases in GIP release and blood glucose excursions. The ability to inhibit both intestinal SGLT1 and renal SGLT2 provides LX4211 with a novel dual mechanism of action for improving glycemic control in patients with T2DM.
    Journal of Pharmacology and Experimental Therapeutics 03/2013; DOI:10.1124/jpet.113.203364 · 3.86 Impact Factor
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    ABSTRACT: BACKGROUND: Combination therapy is required to provide adequate glycemic control in many patients with type 2 diabetes mellitus (T2DM). Because sodium-dependent glucose transporter (SGLT)-1 inhibition results in an increased release of glucagon-like peptide (GLP)-1, and because dipeptidyl peptidase (DPP)-4 inhibitors prevent its inactivation, the 2 mechanisms together provide an intriguing potential combination therapy. OBJECTIVES: This combination was explored in preclinical models and then tested in patients with T2DM to compare the effects of single-dose LX4211 400 mg and sitagliptin 100 mg, administered as monotherapy or in combination, on GLP-1, peptide tyrosine tyrosine (PYY), gastric inhibitory peptide (GIP), glucose, and insulin. METHODS: Preclinical: Obese male C57BL6J mice were assigned to 1 of 4 treatment groups: LX4211 60 mg/kg, sitagliptin 30 mg/kg, LX4211 + sitagliptin, or inactive vehicle. Clinical: This 3-treatment, 3-crossover, randomized, open-label study was conducted at a single center. Patients on metformin monotherapy were washed out from metformin and were randomly assigned to receive sequences of single-dose LX4211, sitagliptin, or the combination. In both studies, blood was collected for the analysis of pharmacodynamic variables (GLP-1, PYY, GIP, glucose, and insulin). In the clinical study, urine was collected to assess urinary glucose excretion. RESULTS: Preclinical: 120 mice were treated and assessed (5/time point/treatment group). With repeat daily dosing, the combination was associated with apparently synergistic increases in active GLP-1 relative to monotherapy with either agent; this finding was supported by findings from an additional 14-day repeated-dose experiment. Clinical: 18 patients were enrolled and treated (mean age, 49 years; 56% male; 89% white). The LX4211 + sitagliptin combination was associated with significantly increased active GLP-1, total GLP-1, and total PYY; with a significant reduction in total GIP; and with a significantly improved blood glucose level, with less insulin, compared with sitagliptin monotherapy. LX4211 was associated with a significant increase in total GLP-1 and PYY and a reduced total GIP, likely due to a reduction in SGLT1-mediated intestinal glucose absorption, whereas sitagliptin was associated with suppression of all 3 peptides relative to baseline. All treatments were well tolerated, with no evidence of diarrhea with LX4211 treatment. CONCLUSIONS: The findings from the preclinical studies suggest that the LX4211 + sitagliptin combination produced synergistic increases in active GLP-1 after a meal challenge containing glucose. These initial clinical results also suggest that a LX4211 + DPP-4 inhibitor combination may provide an option in patients with T2DM. The potential long-term clinical benefits of such combination treatment need to be confirmed in large clinical trials. ClinicalTrials.gov identifier: NCT01441232.
    Clinical Therapeutics 02/2013; DOI:10.1016/j.clinthera.2013.01.010 · 2.59 Impact Factor
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    ABSTRACT: Sodium-glucose cotransporter 2 (SGLT2) is the major, and SGLT1 the minor, transporter responsible for renal glucose reabsorption. Increasing urinary glucose excretion (UGE) by selectively inhibiting SGLT2 improves glycemic control in diabetic patients. We generated Sglt1 and Sglt2 knockout (KO) mice, Sglt1/Sglt2 double KO (DKO) mice, and wildtype (WT) littermates to study their relative glycemic control and to determine contributions of SGLT1 and SGLT2 to UGE. Relative to WTs, Sglt2 KOs had improved oral glucose tolerance and were resistant to streptozotocin-induced diabetes. Sglt1 KOs fed glucose-free high fat diet (G-free HFD) had improved oral glucose tolerance accompanied by delayed intestinal glucose absorption and increased circulating glucagon-like peptide-1 (GLP-1), but had normal tolerance to intraperitoneal glucose. On G-free HFD, Sglt2 KOs had 30%, Sglt1 KOs 2% and WTs < 1% of the UGE of DKO mice. Consistent with their increased UGE, DKOs had lower fasting blood glucose, and improved tolerance to intraperitoneal glucose, compared to Sglt2 KO mice. In conclusion, 1) Sglt2 is the major renal glucose transporter, however Sglt1 reabsorbs 70% of filtered glucose if Sglt2 is absent; 2) mice lacking Sglt2 display improved glucose tolerance despite UGE that is at best 30% of maximum; 3) Sglt1 KO mice respond to oral glucose with increased circulating GLP-1; and 4) mice lacking Sglt1 and Sglt2 have improved glycemic control over mice lacking Sglt2 alone. These data suggest that dual SGLT1/SGLT2 inhibition is an approach that may further improve glycemic control over SGLT2 inhibition alone in patients with type 2 diabetes.
    AJP Endocrinology and Metabolism 11/2012; 304(2). DOI:10.1152/ajpendo.00439.2012 · 4.09 Impact Factor
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    ABSTRACT: Thirty-six patients with type 2 diabetes mellitus (T2DM) were randomized 1:1:1 to receive a once-daily oral dose of placebo or 150 or 300 mg of the dual SGLT1/SGLT2 inhibitor LX4211 for 28 days. Relative to placebo, LX4211 enhanced urinary glucose excretion by inhibiting SGLT2-mediated renal glucose reabsorption; markedly and significantly improved multiple measures of glycemic control, including fasting plasma glucose, oral glucose tolerance, and HbA(1c); and significantly lowered serum triglycerides. LX4211 also mediated trends for lower weight, lower blood pressure, and higher glucagon-like peptide-1 levels. In a follow-up single-dose study in 12 patients with T2DM, LX4211 (300 mg) significantly increased glucagon-like peptide-1 and peptide YY levels relative to pretreatment values, probably by delaying SGLT1-mediated intestinal glucose absorption. In both studies, LX4211 was well tolerated without evidence of increased gastrointestinal side effects. These data support further study of LX4211-mediated dual SGLT1/SGLT2 inhibition as a novel mechanism of action in the treatment of T2DM.
    Clinical Pharmacology &#38 Therapeutics 06/2012; 92(2):158-69. DOI:10.1038/clpt.2012.58 · 7.39 Impact Factor
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    ABSTRACT: There is evidence that genetic factors play a role in the complex multifactorial pathogenesis of hydrocephalus. Identification of the genes involved in the development of this neurologic disorder in animal models may elucidate factors responsible for the excessive accumulation of cerebrospinal fluid in hydrocephalic humans. The authors report here a brief summary of findings from 12 lines of genetically engineered mice that presented with autosomal recessive congenital hydrocephalus. This study illustrates the value of knockout mice in identifying genetic factors involved in the development of congenital hydrocephalus. Findings suggest that dysfunctional motile cilia represent the underlying pathogenetic mechanism in 8 of the 12 lines (Ulk4, Nme5, Nme7, Kif27, Stk36, Dpcd, Ak7, and Ak8). The likely underlying cause in the remaining 4 lines (RIKEN 4930444A02, Celsr2, Mboat7, and transgenic FZD3) was not determined, but it is possible that some of these could also have ciliary defects. For example, the cerebellar malformations observed in RIKEN 4930444A02 knockout mice show similarities to a number of developmental disorders, such as Joubert, Meckel-Gruber, and Bardet-Biedl syndromes, which involve mutations in cilia-related genes. Even though the direct relevance of mouse models to hydrocephalus in humans remains uncertain, the high prevalence of familial patterns of inheritance for congenital hydrocephalus in humans suggests that identification of genes responsible for development of hydrocephalus in mice may lead to the identification of homologous modifier genes and susceptibility alleles in humans. Also, characterization of mouse models can enhance understanding of important cell signaling and developmental pathways involved in the pathogenesis of hydrocephalus.
    Veterinary Pathology 07/2011; 49(1):166-81. DOI:10.1177/0300985811415708 · 2.04 Impact Factor
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    ABSTRACT: Serotonin (5-hydroxytryptamine [5-HT]) has an important role in gastrointestinal function. LX1031 is an oral, locally acting, small molecule inhibitor of tryptophan hydroxylase (TPH). Local inhibition of TPH in the gastrointestinal tract might reduce mucosal production of serotonin (5-HT) and be used to treat patients with nonconstipating irritable bowel syndrome (IBS). We evaluated 2 dose levels of LX1031 (250 mg or 1000 mg, given 4 times/day) in a 28-day, multicenter, randomized, double-blind, placebo-controlled study of 155 patients with nonconstipating IBS. 5-hydroxyindoleacetic acid (5-HIAA), a biomarker of pharmacodynamic activity, was measured in urine samples at baseline (24 hours after LX1031 administration), and at weeks 4 and 6 (n = 76). Each dose of LX1031 was safe and well-tolerated. The primary efficacy end point, relief of IBS pain and discomfort, improved significantly in patients given 1000 mg LX1031 (25.5%), compared with those given placebo, at week 1 (P = .018); with nonsignificant improvements at weeks 2, 3, and 4 (17.9%, 16.3%, and 11.6%, respectively). Symptom improvement correlated with a dose-dependent reduction in 5-HIAA, a marker for TPH inhibition, from baseline until week 4. This suggests the efficacy of LX1031 is related to the extent of inhibition of 5-HT biosynthesis. Stool consistency significantly improved, compared with the group given placebo, at weeks 1 and 4 (P < .01) and at week 2 (P < .001). In a phase 2 study, LX1031 was well tolerated, relieving symptoms and increasing stool consistency in patients with nonconstipating IBS. Symptom relief was associated with reduced levels of 5-HIAA in urine samples. This marker might be used to identify patients with nonconstipating IBS who respond to inhibitors of 5-HT synthesis.
    Gastroenterology 05/2011; 141(2):507-16. DOI:10.1053/j.gastro.2011.05.005 · 13.93 Impact Factor
  • Gastroenterology 05/2010; 138(5). DOI:10.1016/S0016-5085(10)60769-X · 13.93 Impact Factor
  • Gastroenterology 05/2010; 138(5). DOI:10.1016/S0016-5085(10)60592-6 · 13.93 Impact Factor
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    ABSTRACT: Situs inversus (SI) is a congenital condition characterized by left-right transposition of thoracic and visceral organs and associated vasculature. The usual asymmetrical positioning of organs is established early in development in a transient structure called the embryonic node. The 2-cilia hypothesis proposes that 2 kinds of primary cilia in the embryonic node determine left-right asymmetry: motile cilia that generate a leftward fluid flow, and immotile mechanosensory cilia that respond to the flow. Here, we describe 3 mouse SI models that provide support for the 2-cilia hypothesis. In addition to having SI, Dpcd/Poll(-/-) mice (for: deleted in a mouse model of primary ciliary dyskinesia) and Nme7(-/-) mice (for: nonmetastatic cells 7) had lesions consistent with deficient ciliary motility: Hydrocephalus, sinusitis, and male infertility developed in Dpcd/Poll(-/-) mice, whereas hydrocephalus and excessive nasal exudates were seen in Nme7(-/-) mice. In contrast, the absence of respiratory tract lesions, hydrocephalus, and male infertility in Pkd1l1(-/-) mice (for: polycystic kidney disease 1 like 1) suggested that dysfunction of motile cilia was not involved in the development of SI in this line. Moreover, the gene Pkd1l1 has considerable sequence similarity with Pkd1 (for: polycystic kidney disease 1), which encodes a protein (polycystin-1) that is essential for the mechanosensory function of immotile primary cilia in the kidney. The markedly reduced viability of Pkd1l1(-/-) mice is somewhat surprising given the absence of any detected abnormalities (other than SI) in surviving Pkd1l1(-/-) mice subjected to a comprehensive battery of phenotype-screening exams. However, the heart and great vessels of Pkd1l1(-/-) mice were not examined, and it is possible that the decreased viability of Pkd1l1(-/-) mice is due to undiagnosed cardiovascular defects associated with heterotaxy.
    Veterinary Pathology 01/2010; 47(1):120-31. DOI:10.1177/0300985809353553 · 2.04 Impact Factor
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    ABSTRACT: Situs inversus (SI) is characterized by left to right (LR) transposition of thoracic and visceral organs and associated vasculature. The usual asymmetrical positioning of organs is established early in development in a transient structure called the embryonic node. The two-cilia hypothesis proposes that two kinds of cilia in the embryonic node determine LR asymmetry: motile cilia generating leftward fluid flow, and immotile mechanosensory cilia responding to flow. Here we describe three mouse SI models that support the two-cilia hypothesis. In addition to SI, Dpcd-/- mice (for deleted in a mouse model of primary ciliary dyskinesia) and Nme7-/- mice (for non-metastatic cells 7) had lesions consistent with ciliary dyskinesis: hydrocephalus, sinusitis and male infertility developed in Dpcd-/- mice, while hydrocephalus and excessive nasal exudates were seen in Nme7-/- mice. In contrast, the lack of respiratory tract lesions, hydrocephalus, and male infertility in Pkd1l1-/- (for polycystic kidney disease 1 like 1) mice suggested that ciliary dyskinesis was not responsible for SI in this line. Moreover, there is considerable sequence similarity of Pkd1l1 with Pkd1 (for Polycystic kidney disease 1), which encodes a protein (polycystin-1) that is essential for the mechanosensory function of immotile primary cilia in the kidney. The markedly reduced viability of Pkd1l1-/- mice is somewhat surprising given the absence of any detected abnormalities (other than SI) in surviving Pkd1l1-/- mice subjected to comprehensive phenotype screening exams. However, the heart and great vessels of Pkd1l1-/- mice were not examined and it is possible the decreased viability of Pkd1l1-/- mice could be due to undiagnosed cardiovascular defects associated with heterotaxy.
    Veterinary Pathology 09/2009; DOI:10.1354/vp.09-VP-0118-V-AM · 2.04 Impact Factor

Publication Stats

4k Citations
495.03 Total Impact Points

Institutions

  • 2008–2015
    • Lexicon Pharmaceuticals
      The Woodlands, Texas, United States
  • 1994–2015
    • Baylor College of Medicine
      • Department of Molecular & Human Genetics
      Houston, Texas, United States
  • 2010–2014
    • American College of Pathologists
      American Canyon, California, United States
  • 2004
    • Incyte Corporation
      Wilmington, Delaware, United States
    • National Human Genome Research Institute
      Maryland, United States
  • 2001
    • University of Massachusetts Medical School
      Worcester, Massachusetts, United States