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Papers by Eric Bachman

European Journal of Drug Metabolism and Pharmacokinetics

Background and Objective Elexacaftor/tezacaftor/ivacaftor is highly effective in treating people ... more Background and Objective Elexacaftor/tezacaftor/ivacaftor is highly effective in treating people with cystic fibrosis (pwCF) who have ≥ 1 responsive mutation. Liver disease occurs in approximately 10%-20% of pwCF. The objective of this study was to assess the safety and pharmacokinetics of elexacaftor/tezacaftor/ivacaftor in people with moderate hepatic impairment, which is necessary to inform on its use and guide dosing recommendations. Methods The safety and pharmacokinetics of elexacaftor/tezacaftor/ivacaftor were evaluated in subjects without CF with moderate hepatic impairment versus matched healthy controls. Twenty-two subjects (11 with moderate hepatic impairment and 11 healthy subjects) received half the standard adult daily dose of elexacaftor/tezacaftor/ivacaftor (elexacaftor 100 mg/ tezacaftor 50 mg/ivacaftor 150 mg) orally for 10 days. Results Elexacaftor/tezacaftor/ivacaftor was safe and well tolerated in subjects with moderate hepatic impairment and healthy controls. On day 10, the mean values of the area under the curve during the dosing interval (AUC τ) for total (bound and unbound) elexacaftor and its major active metabolite M23-elexacaftor were increased 1.25-fold (95% CI 1.01, 1.54) and 1.73-fold (95% CI 1.27, 2.35), respectively, in subjects with moderate hepatic impairment compared with matched healthy subjects. The mean values of AUC τ for ivacaftor and tezacaftor were increased 1.50-fold (95% CI 1.09, 2.06) and 1.20-fold (95% CI 1.00, 1.43), respectively, while the mean value of AUC τ for the active metabolite M1-tezacaftor was 1.29-fold lower [ratio of moderate hepatic impairment to healthy subjects (95% CI): 0.778 (0.655, 0.924)] in subjects with moderate hepatic impairment. Conclusions A dose reduction of elexacaftor/tezacaftor/ivacaftor is warranted in people with moderate hepatic impairment. (Trial registry number 2018-002570-40; registered 2 July 2018.) Plain Language Summary Elexacaftor/tezacaftor/ivacaftor is a combination product (made up of the three drugs elexacaftor, tezacaftor, and ivacaftor) that can effectively treat cystic fibrosis (CF). About 10%-20% of people with CF have liver disease, and the liver plays an important role in breaking down these drugs. Thus, it is important to understand how liver disease or reduced liver function affects the amounts of these drugs in the body over time. This can help determine how much of the drug (i.e., what dose) people should take.

Journal of Cell Science, 1995

We have investigated the distribution and function of an ezrin-radixin-moesin-like (ERM) molecule... more We have investigated the distribution and function of an ezrin-radixin-moesin-like (ERM) molecule in the sea urchin. A sea urchin homologue of moesin was cloned that shares 75% amino acid similarity in the conserved N-terminal region to other moesin molecules. A 6.3 kb message is transcribed late in embryogenesis and is present in adult tissues. Polyclonal antibodies were generated to proteins expressed by a bacterial expression vector, and affinity purified. These antibodies recognize a single 75 kDa protein that is present throughout development in approximately equal abundance, and specifically they immuno-precipitate a single protein. We show by immunolocalization that SUmoesin has two predominant patterns during development. First, SUmoesin is rapidly redistributed after fertilization from a location throughout the egg cytoplasm to a location in the egg cortex. Later in embryogenesis, SUmoesin is localized to the apical ends of cells in the regions of cell-cell junctions. We sh...

Diabetes, 2018

Background: LIK066 is a potent dual inhibitor of SGLT1/2 (IC50: 20.6 and 0.58 nM for SGLT1 and SG... more Background: LIK066 is a potent dual inhibitor of SGLT1/2 (IC50: 20.6 and 0.58 nM for SGLT1 and SGLT2). We studied mechanistic effects of dual SGLT1/2 inhibition of SGLT1 in the gut and SGLT1/2 in the kidneys. Methods: Effects of LIK066 on weight, glucose and a variety of incretin hormones (GLP-1, PYY, GIP, glucagon, insulin) were investigated in: 1) a single dose cross-over study in T2DM, 2) a 14 day randomized, double-masked study in T2DM, 3) a 12-week randomized, double-masked, placebo-controlled study in obese subjects with normoglycemia (NG) or dysglycemia (DG; HbA1c: ≥5.7% and <10%). Results: LIK066 (2.5, 30, 300 mg single dose) significantly reduced glucose excursion and insulin secretion (p<0.01 at 30 and 300 mg) following oral glucose tolerance test (OGTT) in patients with T2DM (n=12), with the 300 mg dose completely suppressing glucose and insulin excursions. In patients with T2DM (n=30), LIK066 15 mg qd for 14 days reduced blood glucose (41 mg/dL by continuous glucos...

Theriogenology, 1995

The sea urchin embryo follows a relatively simple cell behavioral sequence in its gastrulation mo... more The sea urchin embryo follows a relatively simple cell behavioral sequence in its gastrulation movements. The embryo reaches the gastrula stage as a spherical monolayer of cells. To form the mesoderm, primary mesenchyme cells ingress by delaminating from the vegetal plate, crossing the basal lamina and moving into the central blastocoelar cavity. These cells then migrate along the basal lamina lining the blastocoel and eventually manufacture the skeleton. The presumptive secondary mesenchyme and endoderm invaginate as a tubular sheet of cells from the vegetal pole of the embryo. The archenteron extends across the blastocoel until its tip touches and attaches to the opposite side of the blastocoel. Secondary mesenchyme cells, originally at the tip of the archenteron, differentiate to form a variety of structures including coelomic pouches, esophageal muscles, pigment cells, and other cell types. The endoderm fuses with an invagination of the ventral ectoderm (the stomodaem), to form the mouth and complete the process of gastrulation. A number of experiments have established that these simple morphogenetic movements are accompanied by a number of cell adhesion changes plus a series of cellcell interactions that provide spatial, temporal, and scalar information to cells of the mesoderm and endoderm. The requirement for cell signaling has been demonstrated by manipulative experiments where it has been shown that axial, temporal, spatial, and scalar information is obtained by mesoderm and endoderm from other embryonic cells. That information governs pattern formation and subsequent adhesive changes. This review describes the adhesion changes and the signaling that characterizes this early morphogenesis.

Proceedings of the National Academy of Sciences, 1996

We report the molecular cloning of the first beta-1,3 glucanase from animal tissue. Three peptide... more We report the molecular cloning of the first beta-1,3 glucanase from animal tissue. Three peptide sequences were obtained from beta-1,3 glucanase that had been purified from eggs of the sea urchin Strongylocentrotus purpuratus and the gene was cloned by PCR using oligonucleotides deduced from the peptide sequences. The full-length cDNA shows a predicted enzyme structure of 499 aa with a hydrophobic signal sequence. A 3.2-kb message is present in eggs, during early embryogenesis, and in adult gut tissue. A polyclonal antibody to the native 68-kDa enzyme recognizes a single band during early embryogenesis that reappears in the adult gut, and recognizes a 57-kDa fusion protein made from a full-length cDNA clone for beta-1,3 glucanase. The identity of this molecule as beta-1,3 glucanase is confirmed by sequence homology, by the presence of all three peptide sequences in the deduced amino acid sequence, and by the recognition of the bacterial fusion protein by the antibody directed again...

Blood Advances, 2018

Key Points Ravulizumab provided rapid and sustained reduction in complement-mediated hemolysis at... more Key Points Ravulizumab provided rapid and sustained reduction in complement-mediated hemolysis at dosing intervals up to 12 weeks. Patients receiving higher trough exposures experienced greater frequency of LDH normalization, with no episodes of breakthrough hemolysis.

Cancer Research, 2007

4473 De novo fatty acid synthesis is critical for tumor cell survival, and small molecule inhibit... more 4473 De novo fatty acid synthesis is critical for tumor cell survival, and small molecule inhibitors of this pathway may be useful anti-cancer agents. In this report we sought to evaluate the contributions of two pathway enzymes, acetyl-CoA carboxylase 1 (ACC1) and fatty acid synthase (FAS) on the survival of HCT-116 colon cancer cells. To this end, we performed a kinetic analysis of FAS and ACC1 inhibition using siRNA transfections with two oligonucleotide sequences per target at various concentrations (0, 30 and 60 nM). Cell death (by apoptosis) and viability were assessed and plotted as a function of lipogenesis under the various transfection conditions in order to obtain a specific kinetic profile for knockdown of each enzyme. The resulting curves allowed for a direct comparison of FAS and ACC1 in terms of their significance in maintaining tumor cell viability. A gradual decrease of lipid biosynthesis by as much as 50% was achieved with siRNA-mediated knockdown of either FAS or ...

Blood, 2018

Introduction Ravulizumab, an innovative complement C5 inhibitor given every 8 weeks (q8w), was re... more Introduction Ravulizumab, an innovative complement C5 inhibitor given every 8 weeks (q8w), was recently demonstrated in a large phase 3 study of patients (pts) with paroxysmal nocturnal hemoglobinuria (PNH) and naïve to complement inhibitor therapy to be non-inferior to eculizumab given every 2 weeks (q2w) across all endpoints that measured different aspects of PNH disease (transfusion avoidance [TA], lactate dehydrogenase normalization [LDH-N], percent LDH reduction, breakthrough hemolysis [BTH], Functional Assessment of Chronic Illness Therapy [FACIT]-Fatigue, and hemoglobin stabilization [HGB-S]) (Lee JW et al. EHA Learning Center, Jun 17, 2018; LB2603). PNH pts currently receiving eculizumab may experience treatment burden associated with the q2w dosing regimen. With the development of ravulizumab, PNH pts on prior eculizumab therapy can potentially switch to ravulizumab without interruption of treatment. The primary objective of this study was to assess the noninferiority of ra...

Blood, 2016

Background: ALXN1210 is a humanized monoclonal antibody designed for rapid, complete, sustained i... more Background: ALXN1210 is a humanized monoclonal antibody designed for rapid, complete, sustained inhibition of C5 with less frequent dosing. A previous study in healthy volunteers demonstrated immediate, complete, and sustained C5 inhibition. The terminal half-life of ALXN1210 is approximately 3-4x longer than eculizumab, thus providing continuous suppression of hemolysis with an extended dosing interval. Aims: ALXN1210-PNH-103 is a Phase 1/2, multicenter, open-label, intrapatient dose-escalation study (NCT02598583), evaluating the safety, tolerability, and efficacy of 2 IV maintenance dosing regimens of ALXN1210 in patients (pts) ≥18 y with PNH who were naïve to complement inhibitor therapy. Methods: In this interim analysis, 6 pts in Cohort 1 (C1) received either 400- or 600-mg IV induction doses followed by a 900-mg maintenance dose q4w; 7 pts in Cohort 2 (C2) received 600- and 900-mg induction doses, followed by an 1800-mg maintenance dose q4w for up to 24 wk. The primary efficac...

Diabetes, Obesity and Metabolism, 2019

BACKGROUND: There is an unmet need for a safer and more effective treatment for obesity. This stu... more BACKGROUND: There is an unmet need for a safer and more effective treatment for obesity. This study assessed the effects of licogliflozin, a dual inhibitor of sodium-glucose co-transporter (SGLT) 1/2, on body weight, metabolic parameters and incretin hormones in patients with type 2 diabetes mellitus (T2DM) and/or obesity. METHODS: Patients with obesity (BMI, 35-50 kg/m 2) were enrolled into a 12-week study (N = 88; licogliflozin 150 mg q.d.). Patients with T2DM were enrolled into a second, two-part study, comprising a single-dose cross-over study (N = 12; 2.5 − 300 mg) and a 14-day dosing study (N = 30; 15 mg q.d). Primary endpoints included effects on body weight, effects on glucose, safety and tolerability. Secondary endpoints included urinary glucose excretion (UGE 24) and pharmacokinetics, while exploratory endpoints assessed the effects on incretin hormones (total GLP-1, PYY 3-36 , and GIP), insulin and glucagon. RESULTS: Treatment with licogliflozin 150 mg q.d. for 12 weeks in patients with obesity significantly reduced body weight by 5.7% vs placebo (P < 0.001) and improved metabolic parameters such as significantly reduced postprandial glucose excursion (21%; P < 0.001), reduced insulin levels (80%; P < 0.001) and increased glucagon (59%; P < 0.001). In patients with T2DM, a single dose of licogliflozin 300 mg in the morning prior to an oral glucose tolerance test (OGTT) remarkably reduced glucose excursion by 93% (P < 0.001; incremental AUC 0-4h) and suppressed insulin by 90% (P < 0.01; incremental AUC 0-4h). Treatment with licogliflozin 15 mg q.d. for 14 days reduced 24-hour average glucose levels by 26% (41 mg/dL; P < 0.001) and increased UGE 24 to 100 g (P < 0.001) in patients with T2DM. In addition, this treatment regimen significantly increased total GLP-1 by 54% (P < 0.001) and PYY 3-36 by 67% (P < 0.05) post OGTT vs placebo, while significantly reducing GIP levels by 53% (P < 0.001). Treatment with licogliflozin was generally safe and well tolerated. Diarrhea (increased numbers of loose stool) was the most common adverse event in all studies (90% with licogliflozin vs 25% with placebo in the 12-week study), while a lower incidence of flatulence, abdominal pain and abdominal distension (25%-43% with licogliflozin vs 9%-11% with placebo in the 12-week study) were among the other gastrointestinal events reported. CONCLUSION: Licogliflozin treatment (1-84 days) leads to significant weight loss and favourable changes in a variety of metabolic parameters and incretin hormones. Dual inhibition of SGLT1/2 with licogliflozin in the gut and kidneys is an attractive strategy for treating obesity and diabetes.

Physiological Genomics, 2001

The cDNA of an uncoupling protein (UCP) homolog has been cloned from the swallow-tailed hummingbi... more The cDNA of an uncoupling protein (UCP) homolog has been cloned from the swallow-tailed hummingbird, Eupetomena macroura. The hummingbird uncoupling protein (HmUCP) cDNA was amplified from pectoral muscle (flight muscle) using RT-PCR and primers for conserved domains of various known UCP homologs. The rapid amplification of cDNA ends (RACE) method was used to complete the cloning of the 5′ and 3′ ends of the open reading frame. The HmUCP coding region contains 915 nucleotides, and the deduced protein sequence consists of 304 amino acids, being ∼72, 70, and 55% identical to human UCP3, UCP2, and UCP1, respectively. The uncoupling activity of this novel protein was characterized in yeast. In this expression system, the 12CA5-tagged HmUCP fusion protein was detected by Western blot in the enriched mitochondrial fraction. Similarly to rat UCP1, HmUCP decreased the mitochondrial membrane potential as measured in whole yeast by uptake of the fluorescent potential-sensitive dye 3′,3-dihexy...

Blood, 2018

Ravulizumab, a new complement component C5 inhibitor administered every 8 weeks, was noninferior ... more Ravulizumab, a new complement component C5 inhibitor administered every 8 weeks, was noninferior to eculizumab administered every 2 weeks in complement-inhibitor–naive patients with paroxysmal nocturnal hemoglobinuria (PNH). This study assessed noninferiority of ravulizumab to eculizumab in clinically stable PNH patients during previous eculizumab therapy. In this phase 3, open-label, multicenter study, 195 PNH patients on labeled-dose (900 mg every 2 weeks) eculizumab for >6 months were randomly assigned 1:1 to switch to ravulizumab (n = 97) or continue eculizumab (n = 98). Primary efficacy end point was percentage change in lactate dehydrogenase (LDH) from baseline to day 183. Key secondary end points included proportion of patients with breakthrough hemolysis, change in Functional Assessment of Chronic Illness Therapy (FACIT)–Fatigue score, transfusion avoidance, and stabilized hemoglobin. In 191 patients completing 183 days of treatment, ravulizumab was noninferior to eculizu...

Bone, 2017

The Fibrodysplasia Ossificans Progressiva (FOP) Connection Registry is an international, voluntar... more The Fibrodysplasia Ossificans Progressiva (FOP) Connection Registry is an international, voluntary, observational study that directly captures demographic and disease information initially from patients with FOP (the patient portal) and in the near future from treating physicians (the physician portal) via a secure web-based tool. It was launched by the International FOP Association (IFOPA) with a guiding vision to develop and manage one unified, global, and coordinated Registry allowing the assembly of the most comprehensive data on FOP. This will ultimately facilitate greater access and sharing of patient data and enable better and faster development of therapies and tracking their long-term treatment effectiveness and safety. This report outlines the FOP Connection Registry's design and procedures for data collection and reporting, as well as the long-term sustainability of

Journal of hematology (Brossard, Quebec), 2014

Elmer This is an open-access article distributed under the terms of the Creative Commons Attribut... more Elmer This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited

Contemporary Diabetes

Obesity has emerged as a major threat to human health. Numerous morbidities are associated with o... more Obesity has emerged as a major threat to human health. Numerous morbidities are associated with obesity, including type 2 diabetes mellitus, which now affects adolescents in alarming numbers (1). Understanding the pathogenic mechanisms that lead to obesity, therefore, represents one of the great challenges to medicine today. Obesity is defined arbitrarily as an increase in body fat stores compared to

Endocrinology, 2015

Testosterone treatment induces erythrocytosis that could potentially affect blood viscosity and c... more Testosterone treatment induces erythrocytosis that could potentially affect blood viscosity and cardiovascular risk. We thus investigated the effects of testosterone administration on blood viscosity and erythrocyte deformability using mouse models. Blood viscosity, erythrocyte deformability, and hematocrits were measured in normal male and female mice, as well as in females and castrated males after short-term (2 wk) and long-term (5–7 mo) testosterone intervention (50 mg/kg, weekly). Castrated males for long-term intervention were studied in parallel with the normal males to assess the effect of long-term testosterone deprivation. An additional short-term intervention study was conducted in females with a lower testosterone dose (5 mg/kg). Our results indicate no rheological difference among normal males, females, and castrated males at steady-state. Short-term high-dose testosterone increased hematocrit and whole-blood viscosity in both females and castrated males. This effect di...

The journals of gerontology. Series A, Biological sciences and medical sciences, 2014

The mechanisms by which testosterone increases hemoglobin and hematocrit remain unclear. We asses... more The mechanisms by which testosterone increases hemoglobin and hematocrit remain unclear. We assessed the hormonal and hematologic responses to testosterone administration in a clinical trial in which older men with mobility limitation were randomized to either placebo or testosterone gel daily for 6 months. The 7%-10% increase in hemoglobin and hematocrit, respectively, with testosterone administration was associated with significantly increased erythropoietin (EPO) levels and decreased ferritin and hepcidin levels at 1 and 3 months. At 6 months, EPO and hepcidin levels returned toward baseline in spite of continued testosterone administration, but EPO levels remained nonsuppressed even though elevated hemoglobin and hematocrit higher than at baseline, suggesting a new set point. Consistent with increased iron utilization, soluble transferrin receptor (sTR) levels and ratio of sTR/log ferritin increased significantly in testosterone-treated men. Hormonal and hematologic responses we...

Pain, 2015

Symptomatic androgen deficiency is common in patients taking opioid analgesics, as these drugs po... more Symptomatic androgen deficiency is common in patients taking opioid analgesics, as these drugs potently suppress the hypothalamic-pituitary-gonadal axis. However, the efficacy of testosterone replacement in this setting remains unclear. The objective of this trial was to evaluate the efficacy of testosterone replacement on pain perception and other androgen-dependent outcomes in men with opioid-induced androgen deficiency. We conducted a randomized, double-blind, parallel placebo-controlled trial at an outpatient academic research center. Participants were men aged 18 to 64 years on opioid analgesics for chronic noncancer pain, and total testosterone levels were <350 ng/dL. Participants were randomly assigned to 14 weeks of daily transdermal gel that contained 5 g of testosterone or placebo. Primary outcomes were changes in self-reported clinical pain and objectively assessed pain sensitivity. Sexual function, quality of life, and body composition were also assessed. The mean age was 49 years. The median total and free testosterone levels at baseline were 243 ng/dL and 47 pg/mL and 251 ng/dL and 43 pg/mL in the testosterone and placebo arm, respectively. Of the 84 randomized participants, 65 had follow-up *

PLoS ONE, 2009

Splenic enlargement (splenomegaly) develops in numerous disease states, although a specific patho... more Splenic enlargement (splenomegaly) develops in numerous disease states, although a specific pathogenic role for the spleen has rarely been described. In polycythemia vera (PV), an activating mutation in Janus kinase 2 (JAK2 V617) induces splenomegaly and an increase in hematocrit. Splenectomy is sparingly performed in patients with PV, however, due to surgical complications. Thus, the role of the spleen in the pathogenesis of human PV remains unknown. We specifically tested the role of the spleen in the pathogenesis of PV by performing either sham (SH) or splenectomy (SPL) surgeries in a murine model of JAK2 V617F-driven PV. Compared to SH-operated mice, which rapidly develop high hematocrits after JAK2 V617F transplantation, SPL mice completely fail to develop this phenotype. Disease burden (JAK2 V617) is equivalent in the bone marrow of SH and SPL mice, however, and both groups develop fibrosis and osteosclerosis. If SPL is performed after PV is established, hematocrit rapidly declines to normal even though myelofibrosis and osteosclerosis again develop independently in the bone marrow. In contrast, SPL only blunts hematocrit elevation in secondary, erythropoietin-induced polycythemia. We conclude that the spleen is required for an elevated hematocrit in murine, JAK2 V617F-driven PV, and propose that this phenotype of PV may require a specific interaction between mutant cells and the spleen.

Mechanisms of Ageing and Development, 2005

Reactive oxygen species (ROS) are generated by mitochondrial respiration and can react with and d... more Reactive oxygen species (ROS) are generated by mitochondrial respiration and can react with and damage cellular components. According to the free radical theory of aging, oxidative damage from mitochondrial ROS is a major cause of cellular decline during aging. Mitochondrial uncoupling proteins (UCPs) uncouple ATP production from electron transport and can be stimulated by free radicals, suggesting UCPs may perform a cytoprotective function. The nematode, Caenorhabditis elegans, contains one UCP-like protein, encoded by the ucp-4 gene. We have investigated the genetic requirement for ucp-4 in normal aging and stress resistance. Consistent with the hypothesis that ucp-4 encodes a putative uncoupling protein, animals lacking ucp-4 function contained elevated ATP levels. However, the absence of ucp-4 function did not affect adult lifespan or survival in the presence of thermal or oxidative stress. Together, these results demonstrate that ucp-4 is a negative regulator of ATP production in C. elegans, but is not required for normal lifespan.

European Journal of Drug Metabolism and Pharmacokinetics

Background and Objective Elexacaftor/tezacaftor/ivacaftor is highly effective in treating people ... more Background and Objective Elexacaftor/tezacaftor/ivacaftor is highly effective in treating people with cystic fibrosis (pwCF) who have ≥ 1 responsive mutation. Liver disease occurs in approximately 10%-20% of pwCF. The objective of this study was to assess the safety and pharmacokinetics of elexacaftor/tezacaftor/ivacaftor in people with moderate hepatic impairment, which is necessary to inform on its use and guide dosing recommendations. Methods The safety and pharmacokinetics of elexacaftor/tezacaftor/ivacaftor were evaluated in subjects without CF with moderate hepatic impairment versus matched healthy controls. Twenty-two subjects (11 with moderate hepatic impairment and 11 healthy subjects) received half the standard adult daily dose of elexacaftor/tezacaftor/ivacaftor (elexacaftor 100 mg/ tezacaftor 50 mg/ivacaftor 150 mg) orally for 10 days. Results Elexacaftor/tezacaftor/ivacaftor was safe and well tolerated in subjects with moderate hepatic impairment and healthy controls. On day 10, the mean values of the area under the curve during the dosing interval (AUC τ) for total (bound and unbound) elexacaftor and its major active metabolite M23-elexacaftor were increased 1.25-fold (95% CI 1.01, 1.54) and 1.73-fold (95% CI 1.27, 2.35), respectively, in subjects with moderate hepatic impairment compared with matched healthy subjects. The mean values of AUC τ for ivacaftor and tezacaftor were increased 1.50-fold (95% CI 1.09, 2.06) and 1.20-fold (95% CI 1.00, 1.43), respectively, while the mean value of AUC τ for the active metabolite M1-tezacaftor was 1.29-fold lower [ratio of moderate hepatic impairment to healthy subjects (95% CI): 0.778 (0.655, 0.924)] in subjects with moderate hepatic impairment. Conclusions A dose reduction of elexacaftor/tezacaftor/ivacaftor is warranted in people with moderate hepatic impairment. (Trial registry number 2018-002570-40; registered 2 July 2018.) Plain Language Summary Elexacaftor/tezacaftor/ivacaftor is a combination product (made up of the three drugs elexacaftor, tezacaftor, and ivacaftor) that can effectively treat cystic fibrosis (CF). About 10%-20% of people with CF have liver disease, and the liver plays an important role in breaking down these drugs. Thus, it is important to understand how liver disease or reduced liver function affects the amounts of these drugs in the body over time. This can help determine how much of the drug (i.e., what dose) people should take.

Journal of Cell Science, 1995

We have investigated the distribution and function of an ezrin-radixin-moesin-like (ERM) molecule... more We have investigated the distribution and function of an ezrin-radixin-moesin-like (ERM) molecule in the sea urchin. A sea urchin homologue of moesin was cloned that shares 75% amino acid similarity in the conserved N-terminal region to other moesin molecules. A 6.3 kb message is transcribed late in embryogenesis and is present in adult tissues. Polyclonal antibodies were generated to proteins expressed by a bacterial expression vector, and affinity purified. These antibodies recognize a single 75 kDa protein that is present throughout development in approximately equal abundance, and specifically they immuno-precipitate a single protein. We show by immunolocalization that SUmoesin has two predominant patterns during development. First, SUmoesin is rapidly redistributed after fertilization from a location throughout the egg cytoplasm to a location in the egg cortex. Later in embryogenesis, SUmoesin is localized to the apical ends of cells in the regions of cell-cell junctions. We sh...

Diabetes, 2018

Background: LIK066 is a potent dual inhibitor of SGLT1/2 (IC50: 20.6 and 0.58 nM for SGLT1 and SG... more Background: LIK066 is a potent dual inhibitor of SGLT1/2 (IC50: 20.6 and 0.58 nM for SGLT1 and SGLT2). We studied mechanistic effects of dual SGLT1/2 inhibition of SGLT1 in the gut and SGLT1/2 in the kidneys. Methods: Effects of LIK066 on weight, glucose and a variety of incretin hormones (GLP-1, PYY, GIP, glucagon, insulin) were investigated in: 1) a single dose cross-over study in T2DM, 2) a 14 day randomized, double-masked study in T2DM, 3) a 12-week randomized, double-masked, placebo-controlled study in obese subjects with normoglycemia (NG) or dysglycemia (DG; HbA1c: ≥5.7% and <10%). Results: LIK066 (2.5, 30, 300 mg single dose) significantly reduced glucose excursion and insulin secretion (p<0.01 at 30 and 300 mg) following oral glucose tolerance test (OGTT) in patients with T2DM (n=12), with the 300 mg dose completely suppressing glucose and insulin excursions. In patients with T2DM (n=30), LIK066 15 mg qd for 14 days reduced blood glucose (41 mg/dL by continuous glucos...

Theriogenology, 1995

The sea urchin embryo follows a relatively simple cell behavioral sequence in its gastrulation mo... more The sea urchin embryo follows a relatively simple cell behavioral sequence in its gastrulation movements. The embryo reaches the gastrula stage as a spherical monolayer of cells. To form the mesoderm, primary mesenchyme cells ingress by delaminating from the vegetal plate, crossing the basal lamina and moving into the central blastocoelar cavity. These cells then migrate along the basal lamina lining the blastocoel and eventually manufacture the skeleton. The presumptive secondary mesenchyme and endoderm invaginate as a tubular sheet of cells from the vegetal pole of the embryo. The archenteron extends across the blastocoel until its tip touches and attaches to the opposite side of the blastocoel. Secondary mesenchyme cells, originally at the tip of the archenteron, differentiate to form a variety of structures including coelomic pouches, esophageal muscles, pigment cells, and other cell types. The endoderm fuses with an invagination of the ventral ectoderm (the stomodaem), to form the mouth and complete the process of gastrulation. A number of experiments have established that these simple morphogenetic movements are accompanied by a number of cell adhesion changes plus a series of cellcell interactions that provide spatial, temporal, and scalar information to cells of the mesoderm and endoderm. The requirement for cell signaling has been demonstrated by manipulative experiments where it has been shown that axial, temporal, spatial, and scalar information is obtained by mesoderm and endoderm from other embryonic cells. That information governs pattern formation and subsequent adhesive changes. This review describes the adhesion changes and the signaling that characterizes this early morphogenesis.

Proceedings of the National Academy of Sciences, 1996

We report the molecular cloning of the first beta-1,3 glucanase from animal tissue. Three peptide... more We report the molecular cloning of the first beta-1,3 glucanase from animal tissue. Three peptide sequences were obtained from beta-1,3 glucanase that had been purified from eggs of the sea urchin Strongylocentrotus purpuratus and the gene was cloned by PCR using oligonucleotides deduced from the peptide sequences. The full-length cDNA shows a predicted enzyme structure of 499 aa with a hydrophobic signal sequence. A 3.2-kb message is present in eggs, during early embryogenesis, and in adult gut tissue. A polyclonal antibody to the native 68-kDa enzyme recognizes a single band during early embryogenesis that reappears in the adult gut, and recognizes a 57-kDa fusion protein made from a full-length cDNA clone for beta-1,3 glucanase. The identity of this molecule as beta-1,3 glucanase is confirmed by sequence homology, by the presence of all three peptide sequences in the deduced amino acid sequence, and by the recognition of the bacterial fusion protein by the antibody directed again...

Blood Advances, 2018

Key Points Ravulizumab provided rapid and sustained reduction in complement-mediated hemolysis at... more Key Points Ravulizumab provided rapid and sustained reduction in complement-mediated hemolysis at dosing intervals up to 12 weeks. Patients receiving higher trough exposures experienced greater frequency of LDH normalization, with no episodes of breakthrough hemolysis.

Cancer Research, 2007

4473 De novo fatty acid synthesis is critical for tumor cell survival, and small molecule inhibit... more 4473 De novo fatty acid synthesis is critical for tumor cell survival, and small molecule inhibitors of this pathway may be useful anti-cancer agents. In this report we sought to evaluate the contributions of two pathway enzymes, acetyl-CoA carboxylase 1 (ACC1) and fatty acid synthase (FAS) on the survival of HCT-116 colon cancer cells. To this end, we performed a kinetic analysis of FAS and ACC1 inhibition using siRNA transfections with two oligonucleotide sequences per target at various concentrations (0, 30 and 60 nM). Cell death (by apoptosis) and viability were assessed and plotted as a function of lipogenesis under the various transfection conditions in order to obtain a specific kinetic profile for knockdown of each enzyme. The resulting curves allowed for a direct comparison of FAS and ACC1 in terms of their significance in maintaining tumor cell viability. A gradual decrease of lipid biosynthesis by as much as 50% was achieved with siRNA-mediated knockdown of either FAS or ...

Blood, 2018

Introduction Ravulizumab, an innovative complement C5 inhibitor given every 8 weeks (q8w), was re... more Introduction Ravulizumab, an innovative complement C5 inhibitor given every 8 weeks (q8w), was recently demonstrated in a large phase 3 study of patients (pts) with paroxysmal nocturnal hemoglobinuria (PNH) and naïve to complement inhibitor therapy to be non-inferior to eculizumab given every 2 weeks (q2w) across all endpoints that measured different aspects of PNH disease (transfusion avoidance [TA], lactate dehydrogenase normalization [LDH-N], percent LDH reduction, breakthrough hemolysis [BTH], Functional Assessment of Chronic Illness Therapy [FACIT]-Fatigue, and hemoglobin stabilization [HGB-S]) (Lee JW et al. EHA Learning Center, Jun 17, 2018; LB2603). PNH pts currently receiving eculizumab may experience treatment burden associated with the q2w dosing regimen. With the development of ravulizumab, PNH pts on prior eculizumab therapy can potentially switch to ravulizumab without interruption of treatment. The primary objective of this study was to assess the noninferiority of ra...

Blood, 2016

Background: ALXN1210 is a humanized monoclonal antibody designed for rapid, complete, sustained i... more Background: ALXN1210 is a humanized monoclonal antibody designed for rapid, complete, sustained inhibition of C5 with less frequent dosing. A previous study in healthy volunteers demonstrated immediate, complete, and sustained C5 inhibition. The terminal half-life of ALXN1210 is approximately 3-4x longer than eculizumab, thus providing continuous suppression of hemolysis with an extended dosing interval. Aims: ALXN1210-PNH-103 is a Phase 1/2, multicenter, open-label, intrapatient dose-escalation study (NCT02598583), evaluating the safety, tolerability, and efficacy of 2 IV maintenance dosing regimens of ALXN1210 in patients (pts) ≥18 y with PNH who were naïve to complement inhibitor therapy. Methods: In this interim analysis, 6 pts in Cohort 1 (C1) received either 400- or 600-mg IV induction doses followed by a 900-mg maintenance dose q4w; 7 pts in Cohort 2 (C2) received 600- and 900-mg induction doses, followed by an 1800-mg maintenance dose q4w for up to 24 wk. The primary efficac...

Diabetes, Obesity and Metabolism, 2019

BACKGROUND: There is an unmet need for a safer and more effective treatment for obesity. This stu... more BACKGROUND: There is an unmet need for a safer and more effective treatment for obesity. This study assessed the effects of licogliflozin, a dual inhibitor of sodium-glucose co-transporter (SGLT) 1/2, on body weight, metabolic parameters and incretin hormones in patients with type 2 diabetes mellitus (T2DM) and/or obesity. METHODS: Patients with obesity (BMI, 35-50 kg/m 2) were enrolled into a 12-week study (N = 88; licogliflozin 150 mg q.d.). Patients with T2DM were enrolled into a second, two-part study, comprising a single-dose cross-over study (N = 12; 2.5 − 300 mg) and a 14-day dosing study (N = 30; 15 mg q.d). Primary endpoints included effects on body weight, effects on glucose, safety and tolerability. Secondary endpoints included urinary glucose excretion (UGE 24) and pharmacokinetics, while exploratory endpoints assessed the effects on incretin hormones (total GLP-1, PYY 3-36 , and GIP), insulin and glucagon. RESULTS: Treatment with licogliflozin 150 mg q.d. for 12 weeks in patients with obesity significantly reduced body weight by 5.7% vs placebo (P < 0.001) and improved metabolic parameters such as significantly reduced postprandial glucose excursion (21%; P < 0.001), reduced insulin levels (80%; P < 0.001) and increased glucagon (59%; P < 0.001). In patients with T2DM, a single dose of licogliflozin 300 mg in the morning prior to an oral glucose tolerance test (OGTT) remarkably reduced glucose excursion by 93% (P < 0.001; incremental AUC 0-4h) and suppressed insulin by 90% (P < 0.01; incremental AUC 0-4h). Treatment with licogliflozin 15 mg q.d. for 14 days reduced 24-hour average glucose levels by 26% (41 mg/dL; P < 0.001) and increased UGE 24 to 100 g (P < 0.001) in patients with T2DM. In addition, this treatment regimen significantly increased total GLP-1 by 54% (P < 0.001) and PYY 3-36 by 67% (P < 0.05) post OGTT vs placebo, while significantly reducing GIP levels by 53% (P < 0.001). Treatment with licogliflozin was generally safe and well tolerated. Diarrhea (increased numbers of loose stool) was the most common adverse event in all studies (90% with licogliflozin vs 25% with placebo in the 12-week study), while a lower incidence of flatulence, abdominal pain and abdominal distension (25%-43% with licogliflozin vs 9%-11% with placebo in the 12-week study) were among the other gastrointestinal events reported. CONCLUSION: Licogliflozin treatment (1-84 days) leads to significant weight loss and favourable changes in a variety of metabolic parameters and incretin hormones. Dual inhibition of SGLT1/2 with licogliflozin in the gut and kidneys is an attractive strategy for treating obesity and diabetes.

Physiological Genomics, 2001

The cDNA of an uncoupling protein (UCP) homolog has been cloned from the swallow-tailed hummingbi... more The cDNA of an uncoupling protein (UCP) homolog has been cloned from the swallow-tailed hummingbird, Eupetomena macroura. The hummingbird uncoupling protein (HmUCP) cDNA was amplified from pectoral muscle (flight muscle) using RT-PCR and primers for conserved domains of various known UCP homologs. The rapid amplification of cDNA ends (RACE) method was used to complete the cloning of the 5′ and 3′ ends of the open reading frame. The HmUCP coding region contains 915 nucleotides, and the deduced protein sequence consists of 304 amino acids, being ∼72, 70, and 55% identical to human UCP3, UCP2, and UCP1, respectively. The uncoupling activity of this novel protein was characterized in yeast. In this expression system, the 12CA5-tagged HmUCP fusion protein was detected by Western blot in the enriched mitochondrial fraction. Similarly to rat UCP1, HmUCP decreased the mitochondrial membrane potential as measured in whole yeast by uptake of the fluorescent potential-sensitive dye 3′,3-dihexy...

Blood, 2018

Ravulizumab, a new complement component C5 inhibitor administered every 8 weeks, was noninferior ... more Ravulizumab, a new complement component C5 inhibitor administered every 8 weeks, was noninferior to eculizumab administered every 2 weeks in complement-inhibitor–naive patients with paroxysmal nocturnal hemoglobinuria (PNH). This study assessed noninferiority of ravulizumab to eculizumab in clinically stable PNH patients during previous eculizumab therapy. In this phase 3, open-label, multicenter study, 195 PNH patients on labeled-dose (900 mg every 2 weeks) eculizumab for >6 months were randomly assigned 1:1 to switch to ravulizumab (n = 97) or continue eculizumab (n = 98). Primary efficacy end point was percentage change in lactate dehydrogenase (LDH) from baseline to day 183. Key secondary end points included proportion of patients with breakthrough hemolysis, change in Functional Assessment of Chronic Illness Therapy (FACIT)–Fatigue score, transfusion avoidance, and stabilized hemoglobin. In 191 patients completing 183 days of treatment, ravulizumab was noninferior to eculizu...

Bone, 2017

The Fibrodysplasia Ossificans Progressiva (FOP) Connection Registry is an international, voluntar... more The Fibrodysplasia Ossificans Progressiva (FOP) Connection Registry is an international, voluntary, observational study that directly captures demographic and disease information initially from patients with FOP (the patient portal) and in the near future from treating physicians (the physician portal) via a secure web-based tool. It was launched by the International FOP Association (IFOPA) with a guiding vision to develop and manage one unified, global, and coordinated Registry allowing the assembly of the most comprehensive data on FOP. This will ultimately facilitate greater access and sharing of patient data and enable better and faster development of therapies and tracking their long-term treatment effectiveness and safety. This report outlines the FOP Connection Registry's design and procedures for data collection and reporting, as well as the long-term sustainability of

Journal of hematology (Brossard, Quebec), 2014

Elmer This is an open-access article distributed under the terms of the Creative Commons Attribut... more Elmer This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited

Contemporary Diabetes

Obesity has emerged as a major threat to human health. Numerous morbidities are associated with o... more Obesity has emerged as a major threat to human health. Numerous morbidities are associated with obesity, including type 2 diabetes mellitus, which now affects adolescents in alarming numbers (1). Understanding the pathogenic mechanisms that lead to obesity, therefore, represents one of the great challenges to medicine today. Obesity is defined arbitrarily as an increase in body fat stores compared to

Endocrinology, 2015

Testosterone treatment induces erythrocytosis that could potentially affect blood viscosity and c... more Testosterone treatment induces erythrocytosis that could potentially affect blood viscosity and cardiovascular risk. We thus investigated the effects of testosterone administration on blood viscosity and erythrocyte deformability using mouse models. Blood viscosity, erythrocyte deformability, and hematocrits were measured in normal male and female mice, as well as in females and castrated males after short-term (2 wk) and long-term (5–7 mo) testosterone intervention (50 mg/kg, weekly). Castrated males for long-term intervention were studied in parallel with the normal males to assess the effect of long-term testosterone deprivation. An additional short-term intervention study was conducted in females with a lower testosterone dose (5 mg/kg). Our results indicate no rheological difference among normal males, females, and castrated males at steady-state. Short-term high-dose testosterone increased hematocrit and whole-blood viscosity in both females and castrated males. This effect di...

The journals of gerontology. Series A, Biological sciences and medical sciences, 2014

The mechanisms by which testosterone increases hemoglobin and hematocrit remain unclear. We asses... more The mechanisms by which testosterone increases hemoglobin and hematocrit remain unclear. We assessed the hormonal and hematologic responses to testosterone administration in a clinical trial in which older men with mobility limitation were randomized to either placebo or testosterone gel daily for 6 months. The 7%-10% increase in hemoglobin and hematocrit, respectively, with testosterone administration was associated with significantly increased erythropoietin (EPO) levels and decreased ferritin and hepcidin levels at 1 and 3 months. At 6 months, EPO and hepcidin levels returned toward baseline in spite of continued testosterone administration, but EPO levels remained nonsuppressed even though elevated hemoglobin and hematocrit higher than at baseline, suggesting a new set point. Consistent with increased iron utilization, soluble transferrin receptor (sTR) levels and ratio of sTR/log ferritin increased significantly in testosterone-treated men. Hormonal and hematologic responses we...

Pain, 2015

Symptomatic androgen deficiency is common in patients taking opioid analgesics, as these drugs po... more Symptomatic androgen deficiency is common in patients taking opioid analgesics, as these drugs potently suppress the hypothalamic-pituitary-gonadal axis. However, the efficacy of testosterone replacement in this setting remains unclear. The objective of this trial was to evaluate the efficacy of testosterone replacement on pain perception and other androgen-dependent outcomes in men with opioid-induced androgen deficiency. We conducted a randomized, double-blind, parallel placebo-controlled trial at an outpatient academic research center. Participants were men aged 18 to 64 years on opioid analgesics for chronic noncancer pain, and total testosterone levels were <350 ng/dL. Participants were randomly assigned to 14 weeks of daily transdermal gel that contained 5 g of testosterone or placebo. Primary outcomes were changes in self-reported clinical pain and objectively assessed pain sensitivity. Sexual function, quality of life, and body composition were also assessed. The mean age was 49 years. The median total and free testosterone levels at baseline were 243 ng/dL and 47 pg/mL and 251 ng/dL and 43 pg/mL in the testosterone and placebo arm, respectively. Of the 84 randomized participants, 65 had follow-up *

PLoS ONE, 2009

Splenic enlargement (splenomegaly) develops in numerous disease states, although a specific patho... more Splenic enlargement (splenomegaly) develops in numerous disease states, although a specific pathogenic role for the spleen has rarely been described. In polycythemia vera (PV), an activating mutation in Janus kinase 2 (JAK2 V617) induces splenomegaly and an increase in hematocrit. Splenectomy is sparingly performed in patients with PV, however, due to surgical complications. Thus, the role of the spleen in the pathogenesis of human PV remains unknown. We specifically tested the role of the spleen in the pathogenesis of PV by performing either sham (SH) or splenectomy (SPL) surgeries in a murine model of JAK2 V617F-driven PV. Compared to SH-operated mice, which rapidly develop high hematocrits after JAK2 V617F transplantation, SPL mice completely fail to develop this phenotype. Disease burden (JAK2 V617) is equivalent in the bone marrow of SH and SPL mice, however, and both groups develop fibrosis and osteosclerosis. If SPL is performed after PV is established, hematocrit rapidly declines to normal even though myelofibrosis and osteosclerosis again develop independently in the bone marrow. In contrast, SPL only blunts hematocrit elevation in secondary, erythropoietin-induced polycythemia. We conclude that the spleen is required for an elevated hematocrit in murine, JAK2 V617F-driven PV, and propose that this phenotype of PV may require a specific interaction between mutant cells and the spleen.

Mechanisms of Ageing and Development, 2005

Reactive oxygen species (ROS) are generated by mitochondrial respiration and can react with and d... more Reactive oxygen species (ROS) are generated by mitochondrial respiration and can react with and damage cellular components. According to the free radical theory of aging, oxidative damage from mitochondrial ROS is a major cause of cellular decline during aging. Mitochondrial uncoupling proteins (UCPs) uncouple ATP production from electron transport and can be stimulated by free radicals, suggesting UCPs may perform a cytoprotective function. The nematode, Caenorhabditis elegans, contains one UCP-like protein, encoded by the ucp-4 gene. We have investigated the genetic requirement for ucp-4 in normal aging and stress resistance. Consistent with the hypothesis that ucp-4 encodes a putative uncoupling protein, animals lacking ucp-4 function contained elevated ATP levels. However, the absence of ucp-4 function did not affect adult lifespan or survival in the presence of thermal or oxidative stress. Together, these results demonstrate that ucp-4 is a negative regulator of ATP production in C. elegans, but is not required for normal lifespan.