Lee F Allen - Academia.edu (original) (raw)

Papers by Lee F Allen

Proceedings of the National Academy of Sciences, 1991

The alpha 1B-adrenergic receptor (alpha 1B-ADR) is a member of the G-protein-coupled family of tr... more The alpha 1B-adrenergic receptor (alpha 1B-ADR) is a member of the G-protein-coupled family of transmembrane receptors. When transfected into Rat-1 and NIH 3T3 fibroblasts, this receptor induces focus formation in an agonist-dependent manner. Focus-derived, transformed fibroblasts exhibit high levels of functional alpha 1B-ADR expression, demonstrate a catecholamine-induced enhancement in the rate of cellular proliferation, and are tumorigenic when injected into nude mice. Induction of neoplastic transformation by the alpha 1B-ADR, therefore, identifies this normal cellular gene as a protooncogene. Mutational alteration of this receptor can lead to activation of this protooncogene, resulting in an enhanced ability of agonist to induce focus formation with a decreased latency and quantitative increase in transformed foci. In contrast to cells expressing the wild-type alpha 1B-ADR, focus formation in "oncomutant"-expressing cell lines appears constitutively activated with th...

British Journal of Haematology, 2018

Avatrombopag is an oral thrombopoietin receptor agonist that has been recently approved for treat... more Avatrombopag is an oral thrombopoietin receptor agonist that has been recently approved for treating thrombocytopenia in chronic liver disease patients needing invasive procedures. Clinical trials supporting this new treatment were guided by two double-blind, dose-rising, placebo-controlled Phase 1 studies in healthy adults reported here that assessed safety, tolerability and pharmacokinetic profile of avatrombopag, and its effect on platelet counts. Subjects were randomised (2:1) in the single-dose study (N = 63) to avatrombopag (1, 3, 10, 20, 50, 75 and 100 mg) or placebo, and in the multiple-dose study (N = 29) to avatrombopag (3, 10 and 20 mg) or placebo daily for 14 days. There were no serious adverse events (AEs), dose-limiting toxicities, deaths, AEs causing withdrawal, thromboses or liver function abnormalities. In both studies, avatrombopag peak concentration and exposure increased proportionally relative to dose; half-life was 18-21 h and independent of dose, supporting once-daily dosing. Effects on platelet counts depended on dose, concentration and treatment duration. Platelet count increases began 3-5 days post-administration, with maximum changes of >370 9 10 9 /l over baseline with 20 mg daily after 13-16 days. These data support continued development of avatrombopag for treatment of other thrombocytopenic conditions and provide important guidance for the haematologist in the use of this new thrombopoietin receptor agonist.

International Journal of Hepatology, 2020

Aims. Thrombocytopenia complicates the management of patients with chronic liver disease (CLD) un... more Aims. Thrombocytopenia complicates the management of patients with chronic liver disease (CLD) undergoing invasive procedures with a bleeding risk. Until recently, prophylactic platelet transfusion was the only treatment option, but has significant safety and efficacy limitations. Phase 3 data demonstrated the superiority of avatrombopag to placebo in reducing platelet transfusions for bleeding, supporting its recent approval. Methods. Integrated analyses of pooled data (N=435) from two randomized, double-blind, placebo-controlled, phase 3 studies assessed the original efficacy endpoints. Additional analyses included subgroup analyses, alternate Baseline platelet count definitions, and another efficacy endpoint. Results. Avatrombopag was superior to placebo in increasing patients not requiring a platelet transfusion or rescue procedure, those achieving a platelet count ≥50 × 109/L on Procedure Day, and the change in platelet counts from Baseline. The avatrombopag treatment effect wa...

Journal of Vascular and Interventional Radiology, 2019

Purpose: Lymphatic vessels provide a critical pathway to drain interstitial fluid and participate... more Purpose: Lymphatic vessels provide a critical pathway to drain interstitial fluid and participate immune cell response. We sought to investigate the effects of TAE on lymphatic vessel density in a preclinical model of HCC. Materials: Twenty-four adult male buffalo rats were randomly assigned to receive a fixed dose unloaded beads (70-150 μm) or sham hepatic artery saline infusion. After 7 or 14 days, 6 animals per group were euthanized. Five hotspots located in the tumor were assessed after double immunostaining with podoplanin and Lyve-1, specific markers for lymphatic endothelium. The number of lymphatic vessels per field, area occupied by the vessels, and lumen area were recorded. The data was expressed as median and range of absolute number of lymphatic vessels or area in pixels. Results: Higher lymphatic microvascular density was observed in the group of rats treated with TAE after 14 days with a median vessel number per field of 27 (4-126), followed by bland embolization at 7 days 10 (1-69). In contrast, a similar number of lymphatic vessels was observed in the control group at seven days or at 14 days 8.5 (0-28) versus 8 (1-25) vessels per field; p<0.0001. The largest area occupied by the lymphatic vessels was observed in the group of animals treated with TAE after 14 days 1168.4 (144.92-62598.4), followed by the TAE group at 7 days 1055.5 (358.6-15329.1) and sham control after 14 days 647.25 (90.8-13094.1); p<0.0001. Lymphatic vessels in the group treated with TAE displayed a more dilated lumen compared with controls. Larger lumens were more frequently observed at 14 days after TAE 373.025 (8.422-14247.7) followed by TAE at 7 days 333.385 (37.72-11966.7) when compared with controls after 14 days 132.615 (13.53-9144.7); P ¼ 0.001. Conclusions: Higher lymphatic microvascular density was significantly associated with hepatic artery embolization. Structural and numerical changes were observed in lymphatic vessels after treatment.

Journal of Vascular and Interventional Radiology, 2019

Gastroenterology, Jan 17, 2018

Patients with thrombocytopenia and chronic liver disease (CLD) may require platelet transfusions ... more Patients with thrombocytopenia and chronic liver disease (CLD) may require platelet transfusions before scheduled procedures to decrease risk of bleeding. We performed 2 randomized, placebo-controlled, phase 3 trials in patients with thrombocytopenia and CLD undergoing scheduled procedures to evaluate the safety and efficacy of avatrombopag in increasing platelet counts in this patient population METHODS: In the ADAPT-1 and ADAPT-2 studies, adults with thrombocytopenia and CLD (n=231 and n= 204, respectively) were in 1 of 2 cohorts according to their baseline platelet count (below 40x10/L or 40-50x10/L) and within each cohort randomized (2:1) to 5 daily doses of avatrombopag (60 mg if baseline platelet count below 40x10/L or 40 mg if 40-50x10/L) or placebo. ADAPT-1 was conducted at 75 study sites in 20 countries, from February 2014 through January 2017 and ADAPT-2 was conducted at 74 sites in 16 countries, from December 2013 through January 2017. The primary endpoint was the proport...

Proceedings of the National Academy of Sciences, 1990

Pharmacologic, biochemical, and genetic analyses have demonstrated the existence of multiple alph... more Pharmacologic, biochemical, and genetic analyses have demonstrated the existence of multiple alpha 2-adrenergic receptor (alpha 2AR) subtypes. We have cloned a human alpha 2AR by using the polymerase chain reaction with oligonucleotide primers homologous to conserved regions of the previously cloned alpha 2ARs, the genes for which are located on human chromosomes 4 (C4) and 10 (C10). The deduced amino acid sequence encodes a protein of 450 amino acids whose putative topology is similar to that of the family of guanine nucleotide-binding protein-coupled receptors, but whose structure most closely resembles that of the alpha 2ARs. Competition curve analysis of the binding properties of the receptor expressed in COS-7 cells with a variety of adrenergic ligands demonstrates a unique alpha 2AR pharmacology. Hybridization with somatic cell hybrids shows that the gene for this receptor is located on chromosome 2. Northern blot analysis of various rat tissues shows expression in liver and k...

Blood, 2019

Background: Patients with chronic liver disease (CLD) often have severe thrombocytopenia (platele... more Background: Patients with chronic liver disease (CLD) often have severe thrombocytopenia (platelet counts <50,000/mL) that can complicate the invasive diagnostic and therapeutic procedures these patients require as part of their clinical management, due to the increased bleeding risk. Avatrombopag is a thrombopoietin receptor agonist (TPO-RA) that is approved for the treatment of thrombocytopenia in patients with CLD as an alternative to platelet transfusions for patients undergoing a procedure. The aim of this study was to evaluate the relative cost-effectiveness of avatrombopag compared with platelet transfusion or treatment with lusutrombopag, another TPO-RA also approved for the treatment of thrombocytopenia in adult patients with CLD. Methods: A decision-tree model was developed from a US payer perspective to capture the clinical events observed in registration trials, and to project potential longer-term complications resulting from a major bleed or thromboembolic event in ...

Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2001

To determine the maximum-tolerated dose and characterize the pharmacokinetic behavior of LU79553,... more To determine the maximum-tolerated dose and characterize the pharmacokinetic behavior of LU79553, a novel bisnaphthalimide antineoplastic agent, when administered as a daily intravenous infusion for 5 days every 3 weeks. Patients with advanced solid malignancies received escalating doses of LU79553. Plasma sampling and urine collections were performed on both days 1 and 5 of the first course. Thirty patients received 105 courses of LU79553 at doses ranging from 2 to 24 mg/m(2)/d. Proximal myopathy, erectile dysfunction, and myelosuppression precluded the administration of multiple courses at doses above 18 mg/m(2)/d. These toxicities were intolerable in two of six patients after receiving three courses at the 24-mg/m(2)/d dose level. At the 18-mg/m(2)/d dose, one of six patients developed febrile neutropenia and grade 2 proximal myopathy after three courses of LU79553. The results of electrophysiologic, histopathologic, and ultrastructural studies supported a drug-induced primary my...

Value in Health, 2013

PCS scales implied a 1.02-1.04 RR of hospitalization, a 1.07-1.15 RR of being unable to work, and... more PCS scales implied a 1.02-1.04 RR of hospitalization, a 1.07-1.15 RR of being unable to work, and a 1.04-1.06 RR of losing the ability to work. CONCLUSIONS: Statistical associations with outcomes such as mortality, hospitalization, and work ability can be used as benchmarks to interpret score differences on the SF-36.

Seminars in Oncology, 2002

Nephrology Dialysis Transplantation, 2013

Introduction and Aims: NOX-H94, a PEGylated anti-hepcidin L-RNA oligonucleotide, is in developmen... more Introduction and Aims: NOX-H94, a PEGylated anti-hepcidin L-RNA oligonucleotide, is in development for treatment of anemia of chronic disease (ACD). ACD is frequent in patients with renal failure, cancer, or inflammatory diseases. Caused by high serum hepcidin leading to ferroportin degradation it results in iron sequestration and iron restricted erythropoiesis. Targeting hepcidin may provide an efficacious, well tolerated alternative to current ACD treatments. Methods: NOX-H94 was studied after single and repeated IV and SC doses in healthy men and women. Cohorts of 8 subjects were randomly assigned to single IV doses of 0.3, 0.6, 1.2, 2.4, and 4.8 mg/kg NOX-H94 (n=6) or placebo (n=2), 2 cohorts received 5 q2d IV doses of 0.6 or 1.2 mg/kg NOX-H94, one cohort received 8 q2d SC injections of 0.5 mg/kg NOX-H94. The pharmacodynamics of NOX-H94 were further studied in the human endotoxemia model: 24 healthy young men received 2 ng/kg E. coli endotoxin (LPS) IV to provoke a systemic inflammatory reaction with induction of inflammatory cytokines and subsequently hepcidin, leading to hypoferremia. Subjects were randomly assigned to single double blind IV treatment with 1.2 mg/kg NOX-H94 or placebo 0.5h post LPS. Cytokines and iron parameters were studied; serum iron change at 9h post LPS was the primary endpoint. Results: NOX-H94 doses ≥1.2 mg/kg raised serum iron above placebo LPS induced inflammatory reactions independently of treatment assignment. In the placebo group, iron (19±7.6 µg/L) initially increased until 3h post LPS, the time of hepcidin increase. Iron then decreased to a minimum of 8±2.9 µg/L at 12h. In NOX-H94 treated subjects, iron increased until 6h post LPS (38.3±8.09 µg/L) and remained above baseline until 12h (28.7±9.62 µg/L). Iron concentrations were significantly different from 6 to 12h post LPS (p<0.0001, ANCOVA). Peak and systemic exposures (Cmax and AUC) were largely dose-linear. At 1.2 mg/kg IV Cmax was 2.2±0.3 µM, AUC was 30±6.2 µM×h; T 1/2 was 24±10h. NOX-H94 did not accumulate after repeated doses. After SC injection of 0.5 mg/kg NOX-H94, Cmax was 0.12±0.03 nM 48h post dose and increased almost 3-fold after repeated dosing. Steady state was reached after 4 q2d SC injections. NOX-H94 was well tolerated; mainly headache, fatigue, local reactions, and mild transaminase increases at high doses were observed. Conclusions: These clinical pharmacology studies demonstrated the inhibition of hepcidin by NOX-H94 in humans and showed dose-linear pharmacokinetics and a favourable safety profile. Based on these results, a phase II study in patients with ACD is ongoing.

Journal of Crohn's and Colitis, 2013

Cancer Chemotherapy and Pharmacology, 2000

The dolastatins are a class of naturally occurring cytotoxic peptides which function by inhibitin... more The dolastatins are a class of naturally occurring cytotoxic peptides which function by inhibiting microtubule assembly and tubulin polymerization. Cemadotin is a synthetic analogue of dolastatin 15 with potent antiproliferative and preclinical antitumor activity. This report describes a phase I study to evaluate the administration of cemadotin to adult cancer patients by a 5-day continuous intravenous (CIV) infusion. Methods: All patients had histologically con®rmed refractory solid tumors. The dose was escalated from an initial level of 2.5 mg/m 2 (0.5 mg/m 2 daily) according to a modi®ed Fibonacci algorithm. A minimum of three patients was evaluated at each dose level until the maximum tolerated dose (MTD) was established. Treatment was repeated every 21 days until patients were removed from the study due to toxicity or disease progression. Drug-related toxicities were evaluated and graded by the U.S. National Cancer Institute's Common Toxicity Criteria. A radioimmunoassay (RIA) that detected both the parent drug and its metabolites with an intact N-terminal region of the molecule was used for pharmacokinetic studies. Results: Twenty heavily pretreated patients received a total of 40 courses of cemadotin over ®ve dose levels ranging from 2.5 to 17.5 mg/m 2. Reversible dose-related neutropenia was the principal dose-limiting toxicity and 12.5 mg/m 2 was established as the MTD. Nonhematologic toxicities attributed to the drug were moderate, and there was no evidence of the cardiovascular toxicity noted in the prior phase I studies of cemadotin given IV as a 5-min injection or 24-h infusion. There were no objective antitumor responses. Time courses of the cemadotin RIA equivalent concentration in whole blood were de®ned in 14 patients during the ®rst cycle of therapy. The RIA-detectable species exhibited apparent ®rst-order pharmacokinetics across the entire range of doses. The mean SD of the observed steady-state blood concentration at the 12.5 mg/m 2 MTD was 282 7 nM (n 3). Blood levels decayed monoexponentially following the end of the infusion, with a mean half-life of 13.2 4.3 h (n 14) in all patients. Mean values (n 14) of the total blood clearance and apparent volume of distribution at steady state were 0.52 0.09 l/h/m 2 and 9.9 3.3 l/m 2 , respectively. Conclusions: The cardiotoxic eects of cemadotin were completely avoided by administering it as a 120-h CIV infusion. Thus, cardiovascular toxicity appears to be associated with the magnitude of the peak blood levels of the parent drug or its metabolites, whereas myelotoxicity is related to the duration of time that blood levels exceed a threshold concentration. Nevertheless, the data acquired during the extensive clinical experience with cemadotin requires careful examination to assess whether advancing this compound into disease-oriented ecacy studies is merited.

American Journal of Hematology, 2014

Iron deficiency anemia (IDA) is the most common form of anemia worldwide. Although oral iron is u... more Iron deficiency anemia (IDA) is the most common form of anemia worldwide. Although oral iron is used as first-line treatment, many patients are unresponsive to or cannot take oral iron. This Phase III, open-label, noninferiority study compared the efficacy and safety of ferumoxytol, a rapid, injectable intravenous (IV) iron product with low immunological reactivity and minimal detectable free iron, with IV iron sucrose in adults with IDA of any cause. Patients (N 5 605) were randomized 2:1 to receive ferumoxytol (n 5 406, two doses of 510 mg 5 6 3 days apart) or iron sucrose (n 5 199, five doses of 200 mg on five nonconsecutive days over 14 days) and followed for 5 weeks. Ferumoxytol demonstrated noninferiority to iron sucrose at the primary endpoint, the proportion of patients achieving a hemoglobin increase of 2 g dL 21 at any time from Baseline to Week 5 (ferumoxytol, 84.0% [n 5 406] vs. iron sucrose, 81.4% [n 5 199]), with a noninferiority margin of 15%. Ferumoxytol was superior to iron sucrose (2.7 g dL 21 vs. 2.4 g dL 21) in the mean change in hemoglobin from Baseline to Week 5 (the alternative preplanned primary endpoint) with P 5 0.0124. Transferrin saturation, quality-of-life measures, and safety outcomes were similar between the two treatment groups. Overall, ferumoxytol demonstrated comparable safety and efficacy to iron sucrose, suggesting that ferumoxytol may be a useful treatment option for patients with IDA in whom oral iron was unsatisfactory or could not be used.

American Journal of Hematology, 2013

Although oral iron is the initial treatment approach for iron deficiency anemia (IDA), some patie... more Although oral iron is the initial treatment approach for iron deficiency anemia (IDA), some patients fail to respond to or cannot tolerate oral iron. This double-blind safety and efficacy study of the intravenous (IV) iron, ferumoxytol, randomized patients with a history of unsatisfactory oral iron therapy, or in whom oral iron could not be used, to ferumoxytol (n 5 609) or placebo (n 5 203). The proportion of patients achieving the primary endpoint (hemoglobin increase 2.0 g/dL at Week 5) was 81.1% with ferumoxytol versus 5.5% with placebo (P < 0.0001). The mean increase in hemoglobin from Baseline to Week 5, a secondary endpoint (also the alternative preplanned primary efficacy endpoint for other health authorities), was 2.7 versus 0.1 g/dL (P < 0.0001). Achievement of a hemoglobin 12 g/dL, time to a hemoglobin increase 2.0 g/dL, and improvement in the Functional Assessment of Chronic Illness Therapy Fatigue score also significantly favored ferumoxytol over placebo at Week 5 (P < 0.0001). Ferumoxytol treatment-emergent adverse events were mainly mild to moderate. Ferumoxytol was effective and well tolerated in patients with IDA of any underlying cause in whom oral iron was ineffective or could not be used. This trial was registered at www.clinicaltrials.gov as #NCT01114139.

Blood, 2012

478 Introduction: Iron is essential for the function of many key proteins including hemoglobin (H... more 478 Introduction: Iron is essential for the function of many key proteins including hemoglobin (Hgb) and myoglobin (involved in oxygen transport/exchange), cytochromes (involved in energy generation), various enzymes (involved in cell proliferation and neurotransmission), and immune function. Iron deficiency can, therefore, negatively impact patients' health-related quality of life (HRQL) and requires treatment to replete iron stores. Although oral iron is a common initial treatment, some patients do not tolerate it or fail to adequately respond; many of these patients, therefore, live with chronic anemia and the related negative effects on their overall HRQL. Ferumoxytol (FER) is a new IV iron indicated for the treatment of Iron Deficiency Anemia (IDA) in patients with chronic kidney disease (CKD). FER is being investigated to treat IDA patients without CKD who have a history of unsatisfactory oral iron therapy or in whom oral iron cannot be used. To prospectively explore the i...

Blood, 2015

Background: Peripheral T-cell lymphoma (PTCL) is a heterogeneous group of non-Hodgkin lymphomas a... more Background: Peripheral T-cell lymphoma (PTCL) is a heterogeneous group of non-Hodgkin lymphomas associated with poor prognosis and repeated recurrence for most subtypes. Currently, anthracycline-based therapies such as cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) or CHOP-like therapies are recommended as the first-line treatment for PTCL, but the prognosis remains poor with most patients relapsing within 5 years. Thus, improved treatment strategies are still needed. Belinostat is a potent, pan-histone deacetylase inhibitor that was recently approved in the United States for the treatment of patients with relapsed or refractory PTCL (R/R PTCL). Approval was based on results from the pivotal Phase 2 BELIEF study (O'Connor et al, JCO, 2015) of belinostat in R/R PTCL, which demonstrated durable clinical benefit (objective response rate [ORR] 25.8%) and tolerability. Since belinostat (Bel) and each of the components of the CHOP regimen target different aspects of ...

The Journal of Community and Supportive Oncology, 2016

Effects of IV iron treatment with ferumoxytol on health-related quality of life of patients with ... more Effects of IV iron treatment with ferumoxytol on health-related quality of life of patients with iron deficiency anemia I n the United States and worldwide, iron deficiency anemia (IDA) is one of the most common types of anemia. 1 In industrialized countries, most IDA cases are linked to abnormal uterine bleeding (AUB), gastrointestinal (GI) bleeding, cancer, postpartum bleeding, or chronic kidney disease. 2,3 The etiology of IDA in such patients represents the common pathophysiologic processes that lead to IDA, including blood loss, malabsorption, inadequate iron intake, and inflammatory disease. Iron is essential for the function of many key proteins including hemoglobin (Hb) and myoglobin (involved in oxygen transport and exchange), cytochromes (energy generation), various enzymes (cell proliferation and neurotransmission), and immune function. Iron deficiency can, therefore, have significant physiologic consequences that may have an impact on patients' health-related quality of life (HRQoL). 4,5,6 The impact of disease on people and their experiences as they receive treatments are in many cases best captured through reports from the patients themselves using validated assessment instruments. 7 Many symptoms such as fatigue, depression, or discomfort and their degree of impact

Proceedings of the National Academy of Sciences, 1991

The alpha 1B-adrenergic receptor (alpha 1B-ADR) is a member of the G-protein-coupled family of tr... more The alpha 1B-adrenergic receptor (alpha 1B-ADR) is a member of the G-protein-coupled family of transmembrane receptors. When transfected into Rat-1 and NIH 3T3 fibroblasts, this receptor induces focus formation in an agonist-dependent manner. Focus-derived, transformed fibroblasts exhibit high levels of functional alpha 1B-ADR expression, demonstrate a catecholamine-induced enhancement in the rate of cellular proliferation, and are tumorigenic when injected into nude mice. Induction of neoplastic transformation by the alpha 1B-ADR, therefore, identifies this normal cellular gene as a protooncogene. Mutational alteration of this receptor can lead to activation of this protooncogene, resulting in an enhanced ability of agonist to induce focus formation with a decreased latency and quantitative increase in transformed foci. In contrast to cells expressing the wild-type alpha 1B-ADR, focus formation in "oncomutant"-expressing cell lines appears constitutively activated with th...

British Journal of Haematology, 2018

Avatrombopag is an oral thrombopoietin receptor agonist that has been recently approved for treat... more Avatrombopag is an oral thrombopoietin receptor agonist that has been recently approved for treating thrombocytopenia in chronic liver disease patients needing invasive procedures. Clinical trials supporting this new treatment were guided by two double-blind, dose-rising, placebo-controlled Phase 1 studies in healthy adults reported here that assessed safety, tolerability and pharmacokinetic profile of avatrombopag, and its effect on platelet counts. Subjects were randomised (2:1) in the single-dose study (N = 63) to avatrombopag (1, 3, 10, 20, 50, 75 and 100 mg) or placebo, and in the multiple-dose study (N = 29) to avatrombopag (3, 10 and 20 mg) or placebo daily for 14 days. There were no serious adverse events (AEs), dose-limiting toxicities, deaths, AEs causing withdrawal, thromboses or liver function abnormalities. In both studies, avatrombopag peak concentration and exposure increased proportionally relative to dose; half-life was 18-21 h and independent of dose, supporting once-daily dosing. Effects on platelet counts depended on dose, concentration and treatment duration. Platelet count increases began 3-5 days post-administration, with maximum changes of >370 9 10 9 /l over baseline with 20 mg daily after 13-16 days. These data support continued development of avatrombopag for treatment of other thrombocytopenic conditions and provide important guidance for the haematologist in the use of this new thrombopoietin receptor agonist.

International Journal of Hepatology, 2020

Aims. Thrombocytopenia complicates the management of patients with chronic liver disease (CLD) un... more Aims. Thrombocytopenia complicates the management of patients with chronic liver disease (CLD) undergoing invasive procedures with a bleeding risk. Until recently, prophylactic platelet transfusion was the only treatment option, but has significant safety and efficacy limitations. Phase 3 data demonstrated the superiority of avatrombopag to placebo in reducing platelet transfusions for bleeding, supporting its recent approval. Methods. Integrated analyses of pooled data (N=435) from two randomized, double-blind, placebo-controlled, phase 3 studies assessed the original efficacy endpoints. Additional analyses included subgroup analyses, alternate Baseline platelet count definitions, and another efficacy endpoint. Results. Avatrombopag was superior to placebo in increasing patients not requiring a platelet transfusion or rescue procedure, those achieving a platelet count ≥50 × 109/L on Procedure Day, and the change in platelet counts from Baseline. The avatrombopag treatment effect wa...

Journal of Vascular and Interventional Radiology, 2019

Purpose: Lymphatic vessels provide a critical pathway to drain interstitial fluid and participate... more Purpose: Lymphatic vessels provide a critical pathway to drain interstitial fluid and participate immune cell response. We sought to investigate the effects of TAE on lymphatic vessel density in a preclinical model of HCC. Materials: Twenty-four adult male buffalo rats were randomly assigned to receive a fixed dose unloaded beads (70-150 μm) or sham hepatic artery saline infusion. After 7 or 14 days, 6 animals per group were euthanized. Five hotspots located in the tumor were assessed after double immunostaining with podoplanin and Lyve-1, specific markers for lymphatic endothelium. The number of lymphatic vessels per field, area occupied by the vessels, and lumen area were recorded. The data was expressed as median and range of absolute number of lymphatic vessels or area in pixels. Results: Higher lymphatic microvascular density was observed in the group of rats treated with TAE after 14 days with a median vessel number per field of 27 (4-126), followed by bland embolization at 7 days 10 (1-69). In contrast, a similar number of lymphatic vessels was observed in the control group at seven days or at 14 days 8.5 (0-28) versus 8 (1-25) vessels per field; p<0.0001. The largest area occupied by the lymphatic vessels was observed in the group of animals treated with TAE after 14 days 1168.4 (144.92-62598.4), followed by the TAE group at 7 days 1055.5 (358.6-15329.1) and sham control after 14 days 647.25 (90.8-13094.1); p<0.0001. Lymphatic vessels in the group treated with TAE displayed a more dilated lumen compared with controls. Larger lumens were more frequently observed at 14 days after TAE 373.025 (8.422-14247.7) followed by TAE at 7 days 333.385 (37.72-11966.7) when compared with controls after 14 days 132.615 (13.53-9144.7); P ¼ 0.001. Conclusions: Higher lymphatic microvascular density was significantly associated with hepatic artery embolization. Structural and numerical changes were observed in lymphatic vessels after treatment.

Journal of Vascular and Interventional Radiology, 2019

Gastroenterology, Jan 17, 2018

Patients with thrombocytopenia and chronic liver disease (CLD) may require platelet transfusions ... more Patients with thrombocytopenia and chronic liver disease (CLD) may require platelet transfusions before scheduled procedures to decrease risk of bleeding. We performed 2 randomized, placebo-controlled, phase 3 trials in patients with thrombocytopenia and CLD undergoing scheduled procedures to evaluate the safety and efficacy of avatrombopag in increasing platelet counts in this patient population METHODS: In the ADAPT-1 and ADAPT-2 studies, adults with thrombocytopenia and CLD (n=231 and n= 204, respectively) were in 1 of 2 cohorts according to their baseline platelet count (below 40x10/L or 40-50x10/L) and within each cohort randomized (2:1) to 5 daily doses of avatrombopag (60 mg if baseline platelet count below 40x10/L or 40 mg if 40-50x10/L) or placebo. ADAPT-1 was conducted at 75 study sites in 20 countries, from February 2014 through January 2017 and ADAPT-2 was conducted at 74 sites in 16 countries, from December 2013 through January 2017. The primary endpoint was the proport...

Proceedings of the National Academy of Sciences, 1990

Pharmacologic, biochemical, and genetic analyses have demonstrated the existence of multiple alph... more Pharmacologic, biochemical, and genetic analyses have demonstrated the existence of multiple alpha 2-adrenergic receptor (alpha 2AR) subtypes. We have cloned a human alpha 2AR by using the polymerase chain reaction with oligonucleotide primers homologous to conserved regions of the previously cloned alpha 2ARs, the genes for which are located on human chromosomes 4 (C4) and 10 (C10). The deduced amino acid sequence encodes a protein of 450 amino acids whose putative topology is similar to that of the family of guanine nucleotide-binding protein-coupled receptors, but whose structure most closely resembles that of the alpha 2ARs. Competition curve analysis of the binding properties of the receptor expressed in COS-7 cells with a variety of adrenergic ligands demonstrates a unique alpha 2AR pharmacology. Hybridization with somatic cell hybrids shows that the gene for this receptor is located on chromosome 2. Northern blot analysis of various rat tissues shows expression in liver and k...

Blood, 2019

Background: Patients with chronic liver disease (CLD) often have severe thrombocytopenia (platele... more Background: Patients with chronic liver disease (CLD) often have severe thrombocytopenia (platelet counts <50,000/mL) that can complicate the invasive diagnostic and therapeutic procedures these patients require as part of their clinical management, due to the increased bleeding risk. Avatrombopag is a thrombopoietin receptor agonist (TPO-RA) that is approved for the treatment of thrombocytopenia in patients with CLD as an alternative to platelet transfusions for patients undergoing a procedure. The aim of this study was to evaluate the relative cost-effectiveness of avatrombopag compared with platelet transfusion or treatment with lusutrombopag, another TPO-RA also approved for the treatment of thrombocytopenia in adult patients with CLD. Methods: A decision-tree model was developed from a US payer perspective to capture the clinical events observed in registration trials, and to project potential longer-term complications resulting from a major bleed or thromboembolic event in ...

Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2001

To determine the maximum-tolerated dose and characterize the pharmacokinetic behavior of LU79553,... more To determine the maximum-tolerated dose and characterize the pharmacokinetic behavior of LU79553, a novel bisnaphthalimide antineoplastic agent, when administered as a daily intravenous infusion for 5 days every 3 weeks. Patients with advanced solid malignancies received escalating doses of LU79553. Plasma sampling and urine collections were performed on both days 1 and 5 of the first course. Thirty patients received 105 courses of LU79553 at doses ranging from 2 to 24 mg/m(2)/d. Proximal myopathy, erectile dysfunction, and myelosuppression precluded the administration of multiple courses at doses above 18 mg/m(2)/d. These toxicities were intolerable in two of six patients after receiving three courses at the 24-mg/m(2)/d dose level. At the 18-mg/m(2)/d dose, one of six patients developed febrile neutropenia and grade 2 proximal myopathy after three courses of LU79553. The results of electrophysiologic, histopathologic, and ultrastructural studies supported a drug-induced primary my...

Value in Health, 2013

PCS scales implied a 1.02-1.04 RR of hospitalization, a 1.07-1.15 RR of being unable to work, and... more PCS scales implied a 1.02-1.04 RR of hospitalization, a 1.07-1.15 RR of being unable to work, and a 1.04-1.06 RR of losing the ability to work. CONCLUSIONS: Statistical associations with outcomes such as mortality, hospitalization, and work ability can be used as benchmarks to interpret score differences on the SF-36.

Seminars in Oncology, 2002

Nephrology Dialysis Transplantation, 2013

Introduction and Aims: NOX-H94, a PEGylated anti-hepcidin L-RNA oligonucleotide, is in developmen... more Introduction and Aims: NOX-H94, a PEGylated anti-hepcidin L-RNA oligonucleotide, is in development for treatment of anemia of chronic disease (ACD). ACD is frequent in patients with renal failure, cancer, or inflammatory diseases. Caused by high serum hepcidin leading to ferroportin degradation it results in iron sequestration and iron restricted erythropoiesis. Targeting hepcidin may provide an efficacious, well tolerated alternative to current ACD treatments. Methods: NOX-H94 was studied after single and repeated IV and SC doses in healthy men and women. Cohorts of 8 subjects were randomly assigned to single IV doses of 0.3, 0.6, 1.2, 2.4, and 4.8 mg/kg NOX-H94 (n=6) or placebo (n=2), 2 cohorts received 5 q2d IV doses of 0.6 or 1.2 mg/kg NOX-H94, one cohort received 8 q2d SC injections of 0.5 mg/kg NOX-H94. The pharmacodynamics of NOX-H94 were further studied in the human endotoxemia model: 24 healthy young men received 2 ng/kg E. coli endotoxin (LPS) IV to provoke a systemic inflammatory reaction with induction of inflammatory cytokines and subsequently hepcidin, leading to hypoferremia. Subjects were randomly assigned to single double blind IV treatment with 1.2 mg/kg NOX-H94 or placebo 0.5h post LPS. Cytokines and iron parameters were studied; serum iron change at 9h post LPS was the primary endpoint. Results: NOX-H94 doses ≥1.2 mg/kg raised serum iron above placebo LPS induced inflammatory reactions independently of treatment assignment. In the placebo group, iron (19±7.6 µg/L) initially increased until 3h post LPS, the time of hepcidin increase. Iron then decreased to a minimum of 8±2.9 µg/L at 12h. In NOX-H94 treated subjects, iron increased until 6h post LPS (38.3±8.09 µg/L) and remained above baseline until 12h (28.7±9.62 µg/L). Iron concentrations were significantly different from 6 to 12h post LPS (p<0.0001, ANCOVA). Peak and systemic exposures (Cmax and AUC) were largely dose-linear. At 1.2 mg/kg IV Cmax was 2.2±0.3 µM, AUC was 30±6.2 µM×h; T 1/2 was 24±10h. NOX-H94 did not accumulate after repeated doses. After SC injection of 0.5 mg/kg NOX-H94, Cmax was 0.12±0.03 nM 48h post dose and increased almost 3-fold after repeated dosing. Steady state was reached after 4 q2d SC injections. NOX-H94 was well tolerated; mainly headache, fatigue, local reactions, and mild transaminase increases at high doses were observed. Conclusions: These clinical pharmacology studies demonstrated the inhibition of hepcidin by NOX-H94 in humans and showed dose-linear pharmacokinetics and a favourable safety profile. Based on these results, a phase II study in patients with ACD is ongoing.

Journal of Crohn's and Colitis, 2013

Cancer Chemotherapy and Pharmacology, 2000

The dolastatins are a class of naturally occurring cytotoxic peptides which function by inhibitin... more The dolastatins are a class of naturally occurring cytotoxic peptides which function by inhibiting microtubule assembly and tubulin polymerization. Cemadotin is a synthetic analogue of dolastatin 15 with potent antiproliferative and preclinical antitumor activity. This report describes a phase I study to evaluate the administration of cemadotin to adult cancer patients by a 5-day continuous intravenous (CIV) infusion. Methods: All patients had histologically con®rmed refractory solid tumors. The dose was escalated from an initial level of 2.5 mg/m 2 (0.5 mg/m 2 daily) according to a modi®ed Fibonacci algorithm. A minimum of three patients was evaluated at each dose level until the maximum tolerated dose (MTD) was established. Treatment was repeated every 21 days until patients were removed from the study due to toxicity or disease progression. Drug-related toxicities were evaluated and graded by the U.S. National Cancer Institute's Common Toxicity Criteria. A radioimmunoassay (RIA) that detected both the parent drug and its metabolites with an intact N-terminal region of the molecule was used for pharmacokinetic studies. Results: Twenty heavily pretreated patients received a total of 40 courses of cemadotin over ®ve dose levels ranging from 2.5 to 17.5 mg/m 2. Reversible dose-related neutropenia was the principal dose-limiting toxicity and 12.5 mg/m 2 was established as the MTD. Nonhematologic toxicities attributed to the drug were moderate, and there was no evidence of the cardiovascular toxicity noted in the prior phase I studies of cemadotin given IV as a 5-min injection or 24-h infusion. There were no objective antitumor responses. Time courses of the cemadotin RIA equivalent concentration in whole blood were de®ned in 14 patients during the ®rst cycle of therapy. The RIA-detectable species exhibited apparent ®rst-order pharmacokinetics across the entire range of doses. The mean SD of the observed steady-state blood concentration at the 12.5 mg/m 2 MTD was 282 7 nM (n 3). Blood levels decayed monoexponentially following the end of the infusion, with a mean half-life of 13.2 4.3 h (n 14) in all patients. Mean values (n 14) of the total blood clearance and apparent volume of distribution at steady state were 0.52 0.09 l/h/m 2 and 9.9 3.3 l/m 2 , respectively. Conclusions: The cardiotoxic eects of cemadotin were completely avoided by administering it as a 120-h CIV infusion. Thus, cardiovascular toxicity appears to be associated with the magnitude of the peak blood levels of the parent drug or its metabolites, whereas myelotoxicity is related to the duration of time that blood levels exceed a threshold concentration. Nevertheless, the data acquired during the extensive clinical experience with cemadotin requires careful examination to assess whether advancing this compound into disease-oriented ecacy studies is merited.

American Journal of Hematology, 2014

Iron deficiency anemia (IDA) is the most common form of anemia worldwide. Although oral iron is u... more Iron deficiency anemia (IDA) is the most common form of anemia worldwide. Although oral iron is used as first-line treatment, many patients are unresponsive to or cannot take oral iron. This Phase III, open-label, noninferiority study compared the efficacy and safety of ferumoxytol, a rapid, injectable intravenous (IV) iron product with low immunological reactivity and minimal detectable free iron, with IV iron sucrose in adults with IDA of any cause. Patients (N 5 605) were randomized 2:1 to receive ferumoxytol (n 5 406, two doses of 510 mg 5 6 3 days apart) or iron sucrose (n 5 199, five doses of 200 mg on five nonconsecutive days over 14 days) and followed for 5 weeks. Ferumoxytol demonstrated noninferiority to iron sucrose at the primary endpoint, the proportion of patients achieving a hemoglobin increase of 2 g dL 21 at any time from Baseline to Week 5 (ferumoxytol, 84.0% [n 5 406] vs. iron sucrose, 81.4% [n 5 199]), with a noninferiority margin of 15%. Ferumoxytol was superior to iron sucrose (2.7 g dL 21 vs. 2.4 g dL 21) in the mean change in hemoglobin from Baseline to Week 5 (the alternative preplanned primary endpoint) with P 5 0.0124. Transferrin saturation, quality-of-life measures, and safety outcomes were similar between the two treatment groups. Overall, ferumoxytol demonstrated comparable safety and efficacy to iron sucrose, suggesting that ferumoxytol may be a useful treatment option for patients with IDA in whom oral iron was unsatisfactory or could not be used.

American Journal of Hematology, 2013

Although oral iron is the initial treatment approach for iron deficiency anemia (IDA), some patie... more Although oral iron is the initial treatment approach for iron deficiency anemia (IDA), some patients fail to respond to or cannot tolerate oral iron. This double-blind safety and efficacy study of the intravenous (IV) iron, ferumoxytol, randomized patients with a history of unsatisfactory oral iron therapy, or in whom oral iron could not be used, to ferumoxytol (n 5 609) or placebo (n 5 203). The proportion of patients achieving the primary endpoint (hemoglobin increase 2.0 g/dL at Week 5) was 81.1% with ferumoxytol versus 5.5% with placebo (P < 0.0001). The mean increase in hemoglobin from Baseline to Week 5, a secondary endpoint (also the alternative preplanned primary efficacy endpoint for other health authorities), was 2.7 versus 0.1 g/dL (P < 0.0001). Achievement of a hemoglobin 12 g/dL, time to a hemoglobin increase 2.0 g/dL, and improvement in the Functional Assessment of Chronic Illness Therapy Fatigue score also significantly favored ferumoxytol over placebo at Week 5 (P < 0.0001). Ferumoxytol treatment-emergent adverse events were mainly mild to moderate. Ferumoxytol was effective and well tolerated in patients with IDA of any underlying cause in whom oral iron was ineffective or could not be used. This trial was registered at www.clinicaltrials.gov as #NCT01114139.

Blood, 2012

478 Introduction: Iron is essential for the function of many key proteins including hemoglobin (H... more 478 Introduction: Iron is essential for the function of many key proteins including hemoglobin (Hgb) and myoglobin (involved in oxygen transport/exchange), cytochromes (involved in energy generation), various enzymes (involved in cell proliferation and neurotransmission), and immune function. Iron deficiency can, therefore, negatively impact patients' health-related quality of life (HRQL) and requires treatment to replete iron stores. Although oral iron is a common initial treatment, some patients do not tolerate it or fail to adequately respond; many of these patients, therefore, live with chronic anemia and the related negative effects on their overall HRQL. Ferumoxytol (FER) is a new IV iron indicated for the treatment of Iron Deficiency Anemia (IDA) in patients with chronic kidney disease (CKD). FER is being investigated to treat IDA patients without CKD who have a history of unsatisfactory oral iron therapy or in whom oral iron cannot be used. To prospectively explore the i...

Blood, 2015

Background: Peripheral T-cell lymphoma (PTCL) is a heterogeneous group of non-Hodgkin lymphomas a... more Background: Peripheral T-cell lymphoma (PTCL) is a heterogeneous group of non-Hodgkin lymphomas associated with poor prognosis and repeated recurrence for most subtypes. Currently, anthracycline-based therapies such as cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) or CHOP-like therapies are recommended as the first-line treatment for PTCL, but the prognosis remains poor with most patients relapsing within 5 years. Thus, improved treatment strategies are still needed. Belinostat is a potent, pan-histone deacetylase inhibitor that was recently approved in the United States for the treatment of patients with relapsed or refractory PTCL (R/R PTCL). Approval was based on results from the pivotal Phase 2 BELIEF study (O'Connor et al, JCO, 2015) of belinostat in R/R PTCL, which demonstrated durable clinical benefit (objective response rate [ORR] 25.8%) and tolerability. Since belinostat (Bel) and each of the components of the CHOP regimen target different aspects of ...

The Journal of Community and Supportive Oncology, 2016

Effects of IV iron treatment with ferumoxytol on health-related quality of life of patients with ... more Effects of IV iron treatment with ferumoxytol on health-related quality of life of patients with iron deficiency anemia I n the United States and worldwide, iron deficiency anemia (IDA) is one of the most common types of anemia. 1 In industrialized countries, most IDA cases are linked to abnormal uterine bleeding (AUB), gastrointestinal (GI) bleeding, cancer, postpartum bleeding, or chronic kidney disease. 2,3 The etiology of IDA in such patients represents the common pathophysiologic processes that lead to IDA, including blood loss, malabsorption, inadequate iron intake, and inflammatory disease. Iron is essential for the function of many key proteins including hemoglobin (Hb) and myoglobin (involved in oxygen transport and exchange), cytochromes (energy generation), various enzymes (cell proliferation and neurotransmission), and immune function. Iron deficiency can, therefore, have significant physiologic consequences that may have an impact on patients' health-related quality of life (HRQoL). 4,5,6 The impact of disease on people and their experiences as they receive treatments are in many cases best captured through reports from the patients themselves using validated assessment instruments. 7 Many symptoms such as fatigue, depression, or discomfort and their degree of impact