scholarly journals The Pharmacokinetics, Pharmacodynamics, and Safety of Intravenous Pegcetacoplan Treatment in Healthy Subjects

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4304-4304
Author(s):  
Federico Grossi ◽  
Michael Yeh ◽  
Raymond Xu ◽  
Pascal Deschatelets
Keyword(s):  
Adverse Events ◽  
Hemolytic Activity ◽  
Healthy Subjects ◽  
Sodium Acetate Solution ◽  
Complement Cascade ◽  
Acetate Solution ◽  
Publicly Traded ◽  
Post Dose ◽  
Complement Activity ◽  
Saline Treatment

Abstract Background: The complement cascade is part of innate immunity and is involved in multiple inflammatory processes and implicated in several diseases. Pegcetacoplan (PEG) is a pegylated, cyclic peptide that binds to complement protein C3 and is a broad inhibitor of the complement cascade. Subcutaneous (SC) dosing of PEG has demonstrated efficacy in the treatment of chronic conditions, such as paroxysmal nocturnal hemoglobinuria (PNH) and was recently approved by the FDA for the treatment of PNH in adults. Intravenous (IV) PEG administration may allow for more rapid and robust reduction of uncontrolled complement activation, especially in an acute setting, such as an acute hemolytic episode in PNH. Aims: To determine the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of IV PEG in acetate-buffered saline treatment in a Phase 1 single ascending dose study (ACTRN12616000700437) in healthy subjects. Methods: On Day 1, four cohorts with PEG doses (200mg, 600mg, 1500mg, 2300mg) received a single bolus of PEG IV (or matching placebo) administered over 30min. Blood samples for PK analyses of PEG concentration and PD analyses of alternative complement pathway hemolytic activity (AH50), total complement hemolytic activity (CH50), C3 and C3a levels were collected at 15, 30, and 60min, 4, 8, 12, and 24hrs, and Days 3, 4, 5, 6, 7, 8, 15, 22, 29, and 43. Subjects were monitored during a safety period from Day 2 to 8 by physical examination, ECG, hematology, serum chemistry, monitoring for injection site reaction and treatment emergent adverse events (TEAEs). Follow-up safety assessments were performed on Days 15, 22, 29, and 43. Results: Twenty subjects were enrolled and allocated 4:1 to PEG or placebo per cohort (PEG-200mg, n=4; PEG-600mg, n=4; PEG-1500mg, n=4; PEG-2300mg, n=4; pooled placebo, n=4). Following a single IV dose, peak concentration (C max) of PEG was observed at 1hr post-dose (infusion start) for most cohorts (mean serum concentration: PEG-200mg, 61μg/mL; PEG-600mg, 193μg/mL; PEG-2300mg, 708μg/mL) except PEG-1500mg (occurred at 4hrs, 542μg/mL). PEG concentration at the end of infusion was similar to the observed C max. PEG concentration declined in a mono-exponential manner, with a terminal elimination half-life ranging from 200 to 285 hrs (Figure). Total body clearance of PEG after IV administration was similar across cohorts. Early, immediate decreases in mean AH50 values were detected within 1hr in all PEG cohorts, with 1500 and 2300mg doses decreasing AH50 to undetectable levels (Figure). Decreases in mean AH50 values were maintained for at least 12, 72, 144 and 168hrs after single doses of 200, 600, 1500 and 2300mg PEG, respectively. All PEG groups had an initial rapid decrease within 1hr in mean C3a levels, with all dose groups having trough mean C3a levels within 24hrs of dosing. Dose related decreases in mean C3a were not observed, all doses recorded a max mean decrease of 47% to 57%. No changes seen with placebo for C3a. C3 and CH50 results will be forthcoming. Of the twenty subjects included in the study, 11 (55.0%) experienced a treatment-related adverse event (TEAE). The most common TEAEs in the PEG group were headache, (n=6, 37.5%); upper respiratory infections attributed to seasonal viral infection (n=2, 12.5%); diarrhea (n=2, 12.5%). No serious adverse events, deaths, or severe TEAEs occurred. One subject (5.0%) in the PEG-2300mg cohort experienced a moderate TEAE (infusion-related reaction, dizziness, clamminess, nausea) that led to study discontinuation. Conclusions: These results suggest that administration of IV PEG in a sodium acetate solution has a favorable safety profile and effectively increases PEG serum concentrations while decreasing complement activity within the first hour post-dose in healthy subjects. Although the safety and efficacy of SC PEG treatment has been demonstrated in patients with PNH, IV PEG administration could serve as a useful therapeutic option for patients with a need for rapid control of complement activity. While this formulation is different than the commercially available PEG (EMPAVELI), which is administered SC and is suspended in sorbitol, the results suggest that IV PEG is well tolerated and provides the grounds for future investigations of IV PEG administration. Figure 1 Figure 1. Disclosures Grossi: Apellis Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Yeh: Apellis Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Xu: Apellis Pharmaceuticals: Current Employment. Deschatelets: Apellis Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. OffLabel Disclosure: Pegcetacoplan, a subcutaneously administered C3-inhibitor that was recently approved by the US FDA for the treatment of PNH, controls IVH and prevents EVH. While subcutaneous pegcetacoplan is safe and effective, the aim of this study was to determine the safety, pharmacokinetics, and pharmacodynamics of IV pegcetacoplan in acetate-buffered saline treatment, different from current FDA approved formulation.

Phase 1 Rising Multiple-Dose Study of Talabostat (PT-100) in Healthy Subjects.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4215-4215 ◽  
Author(s):  
Margaret J. Uprichard ◽  
Barry Jones
Keyword(s):  
Adverse Events ◽  
Healthy Subjects ◽  
Significant Inhibition ◽  
Average Increase ◽  
Healthy Male ◽  
Post Dose ◽  
Peripheral Edema ◽  
Dpp Iv ◽  
Limit Of Quantitation ◽  
Male Subjects

Abstract Background: Talabostat (PT-100) is an orally available small molecule that competitively inhibits dipeptidyl peptidases such as DPP-IV/CD26 and fibroblast activation protein (FAP). In vitro, talabostat promotes proliferation of hematopoietic progenitor cells. In vivo it stimulates expansion of progenitors in both white and red cell lineages and causes tumor regression in mouse models. Talabostat has also been shown to accelerate neutrophil recovery in patients and mice receiving myelosuppressive chemotherapy. Its activity appears to be mediated via rapid upregulation of cytokine and chemokine (e.g., G-CSF, IL-6, IL-8) production. Methods: This randomized, placebo-controlled, sequential, dose-escalation study was conducted to evaluate the pharmacodynamics and safety of talabostat in healthy male subjects. 48 healthy male subjects aged 19 to 44 years were randomized to receive daily doses of either 25-, 100-, 300-, 600-, 1200-, 1800μg talabostat or placebo for 7 days. Subjects were randomized in cohorts of 8 subjects each in a 6:2 (talabostat: placebo) scheme. Pharmacodynamics were assessed by measurement of plasma DPP-IV activity, plasma G-CSF, IL-6 and IL-11, and white blood cell (WBC), and absolute neutrophil counts (ANC) at specified timepoints intervals during the study. Clinical examinations, laboratories, vitals, ECG, and adverse events (AEs) were evaluated at specified intervals. Results: At 30 minutes post-dose, talabostat doses ≥ 100μg showed a dose-related, sustained, significant inhibition of DPP-IV activity to 75% to 95% of baseline (p<0.001) in healthy subjects. On Day 1, there was a significant increase in IL-6 at 6 and 12 hours post-dose across all dose cohorts (p<0.01). At 6 and 12 hours, respectively, an average increase in IL-6 of 1426% and 2130% relative to baseline was observed (p<0.05). There was a dose-related increase in G-CSF, with significant increases at doses ≥600μg noted pre-dose on Day 4 (p<0.05). Across all groups on Day 1, an average increase in G-CSF of 132% was noted at 6 hours. Only modest changes in WBC and ANC were noted in these healthy subjects. IL-11 remained unchanged or below the limit of quantitation. The most frequent AEs across all cohorts were (talabostat vs placebo): headache 19/36 (53%) vs 4/12 (33%), myalgia 9/36 (25%) vs 1/12 (8%), nausea 6/36 (17%) vs 0, vomiting 5/36 (14%) vs 1/12 (8%), peripheral edema 5/36 (14%) vs 0, rigors 5/36 (14%) vs 0, sore throat 4/36 (11%) vs 1 (8%)., and arthralgia 4/36 (11%) vs 0. Peripheral edema, myalgia, arthralgia, and rigors were dose-related with all but one event of peripheral edema occurring at talabostat single doses ≥1200μg. There were no serious AEs. The talabostat 1800μg dose cohort was terminated after 2 doses due to adverse events of edema, and talabostat 1200μg was considered the maximum tolerated dose. Conclusion: Talabostat doses ≥100μg showed significant inhibition of DPP-IV activity. Significant dose-related increases in IL-6 and G-CSF were observed. ANC and WBC counts did not change significantly in healthy subjects over the 7-day study. Multiple doses of talabostat were well-tolerated. These results support conducting additional clinical studies in patients to further evaluate the hematopoietic effects of talabostat.

scholarly journals Safety, Tolerability, and Clinical Pharmacology of ANX009, an Inhibitory Antibody Fab Fragment Against C1q, Administered Subcutaneously to Healthy Volunteers

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3166-3166
Author(s):  
Anita Grover ◽  
Jeffrey Teigler ◽  
Emily Radomile ◽  
Shawn Rose ◽  
Ted Yednock ◽  
...  
Keyword(s):  
Clinical Pharmacology ◽  
Adverse Events ◽  
Healthy Volunteers ◽  
Complement Activation ◽  
Ex Vivo ◽  
Phase 1 ◽  
Complement Cascade ◽  
Publicly Traded ◽  
Full Reduction ◽  
Classical Complement

Abstract Certain autoantibodies that bind to tissue antigens or that deposit in tissues as a component of immune complexes can activate the classical complement cascade, leading to inflammation and tissue damage. As the initiating molecule of the classical complement cascade, C1q is an attractive target for preventing complement activation and its multiple tissue-damaging effects. ANX009 is an antigen binding fragment (Fab) of a humanized antibody against C1q that inhibits C1q substrate interactions and fully blocks activation of all downstream classical complement components. While inhibiting the classical cascade, ANX009 leaves the lectin and alternative complement pathways intact for their normal immune functions. ANX009 is formulated for subcutaneous (SC) administration and is designed for treatment of blood-based and vascular antibody-mediated autoimmune diseases, such as autoimmune hemolytic anemia (AIHA) and lupus nephritis, where complement activation is a key component of disease pathology. A phase 1 first-in-human single ascending dose (SAD) and multiple ascending dose (MAD) study of ANX009 with subcutaneous administration was conducted in 48 healthy volunteers (NCT04535752). Four SAD cohorts were enrolled followed by two MAD cohorts evaluating daily dosing for 7 days or twice weekly dosing x 4 doses. Each cohort had eight participants randomized in a 6:2 active:placebo ratio. Safety and tolerability were assessed, along with serum pharmacokinetics (unbound drug), pharmacodynamics (unbound C1q target), and an ex vivo measure of C1q activity (CH 50 hemolysis of antibody-sensitized sheep red blood cells). All dose levels were well-tolerated. No drug-related safety signals, dose-limiting toxicities, serious adverse events, or adverse events leading to discontinuations were observed. Mild, transient, local injection site reactions were observed. A clear dose-response relationship was observed in SAD cohorts. Negligible reduction in free C1q was observed in the two lowest dose cohorts. A maximum mean reduction in free C1q of 80% was observed at 48 hours post-dose at the third dose level, and full reduction of free C1q through 72 hours was observed at the highest dose level. Similarly, full reduction of free C1q was observed in the MAD cohort with daily dosing as well as in the second MAD cohort with twice weekly dosing. Full reduction of C1q was maintained for 4 days following the last dose in the second MAD cohort. Ex vivo functional activity of C1q was completely inhibited in close correspondence with free C1q levels. Combined safety, tolerability, and clinical pharmacology results from this phase 1 study support advancement of ANX009 to studies in patients with complement-mediated autoimmune disorders. Disclosures Grover: Annexon Inc: Current Employment, Current equity holder in publicly-traded company. Teigler: Annexon Inc: Current Employment, Current equity holder in publicly-traded company. Radomile: Annexon Inc: Current Employment, Current equity holder in publicly-traded company. Rose: Annexon Inc: Current Employment, Current equity holder in publicly-traded company. Yednock: Annexon Inc: Current Employment, Current equity holder in publicly-traded company. Keswani: Annexon Inc: Current Employment, Current equity holder in publicly-traded company.

Safety and Pharmacokinetics of Ruxolitinib (INC424) in Healthy Japanese Volunteers: Placebo-Controlled, Double-Blind, Dose-Escalation Phase 1 Study

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 5162-5162
Author(s):  
Yoichiro Ogama ◽  
Tomoko Mineyame ◽  
Asuka Yamamoto ◽  
Naomi Shimada ◽  
Taro Amagasaki ◽  
...  
Keyword(s):  
Single Dose ◽  
Plasma Concentration ◽  
Adverse Events ◽  
Half Life ◽  
Healthy Subjects ◽  
Phase 1 ◽  
Maximum Plasma ◽  
Post Dose ◽  
To Receive ◽  
Dose Reductions

Abstract Abstract 5162 Background: Ruxolitinib (INC424), a potent and selective oral JAK1 and JAK2 inhibitor, demonstrated rapid and durable reductions in splenomegaly and improved disease-related symptoms, role functioning, and quality of life (QoL) in 2 phase 3 studies in patients with myelofibrosis (MF) (the COMFORT studies). The safety, tolerability, and pharmacokinetics (PK) of ruxolitinib have been evaluated in non-Asian healthy subjects. However, its ethnic sensitivity has not been investigated. This is the first study in Japan to evaluate the safety, tolerability, and PK of ruxolitinib in healthy Japanese volunteers. Methods: There were 4 dose cohorts with 10 male subjects in each, 8 randomized to receive ruxolitinib and 2 randomized to receive placebo. In cohort 1 (10 mg) and cohort 2 (25 mg), each subject received a single dose (QD) of ruxolitinib or placebo on day 1 and received twice daily (bid) doses on days 4 through 10. In cohorts 3 and 4, subjects received a single dose of ruxolitinib (50 and 100 mg, respectively) or placebo on day 1. Serial blood samples for PK analysis were collected up to 48 hours post-dose, and ruxolitinib concentrations were analyzed by a validated liquid chromatography-tandem mass spectrometry assay. PK parameters were derived from individual plasma concentration time data using non-compartmental analysis. Adverse events (AEs) were assessed according to the Common Terminology Criteria for Adverse Events version 3.0. Results: The median age of the 40 enrolled healthy subjects was 27 years. Ruxolitinib was rapidly absorbed (Cmax achieved 0.5 hours after dosing), and exposure increased dose proportionally between 10 and 100 mg (Table). Consistent with the half-life of 2–3 hours and a 12-hour dosing interval, drug accumulation was not observed after repeated dosing. These results are similar to those obtained in non-Japanese healthy volunteers (Shi JG, et al. J Clin Pharmacol, May 20, 2011 [epub ahead of print]). AUC(0–¥), area under the curve from zero to infinity; Cmax, maximum plasma concentration; t1/2, half-life; CL/F, apparent total body clearance. Consistent with ruxolitinib's inhibition of the JAK pathway, grade 2 decreases in absolute neutrophil counts were observed in 5 subjects (3 in the 10-mg bid cohort, 1 in the 25-mg bid cohort, and 1 in the 100-mg QD cohort). However, these neutrophil decreases were managed with dose reductions in 2 subjects (1 each in the 10- and 25-mg bid cohorts) or without dose reductions in 3 subjects and rapidly recovered after the last administration of the study drug. Laboratory values showed that a similar decrease in neutrophils was also observed in subjects randomized to placebo. One subject (25-mg bid cohort) experienced a grade 1 increase in alanine aminotransferase 3 days following the last dose. All AEs resolved during the study without any treatment and were not dose dependent. Conclusions: Orally administered ruxolitinib has a predictable PK and is well tolerated in healthy Japanese volunteers. There are no apparent ethnic differences in the PK of ruxolitinib between Japanese and non-Japanese subjects. Disclosures: Shimada: Novartis Pharma K.K.: Employment. Amagasaki:Novartis Pharma K.K.: Employment. Natsume:Novartis Pharma K.K.: Employment.

scholarly journals Structure of aqueous sodium acetate solutions by X-Ray scattering and density functional theory

2020 ◽  
Vol 92 (10) ◽  
pp. 1627-1641
Author(s):  
Guangguo Wang ◽  
Yongquan Zhou ◽  
He Lin ◽  
Zhuanfang Jing ◽  
Hongyan Liu ◽  
...  
Keyword(s):  
Sodium Acetate ◽  
Density Functional ◽  
Hydration Shell ◽  
Ion Pair ◽  
Water Molecules ◽  
Sodium Acetate Solution ◽  
Acetate Solution ◽  
X Ray ◽  
X Ray Scattering ◽  
Ray Scattering

AbstractThe structure of aq. sodium acetate solution (CH3COONa, NaOAc) was studied by X-ray scattering and density function theory (DFT). For the first hydrated layer of Na+, coordination number (CN) between Na+ and O(W, I) decreases from 5.02 ± 0.85 at 0.976 mol/L to 3.62 ± 1.21 at 4.453 mol/L. The hydration of carbonyl oxygen (OC) and hydroxyl oxygen (OOC) of CH3COO− were investigated separately and the OC shows a stronger hydration bonds comparing with OOC. With concentrations increasing, the hydration shell structures of CH3COO− are not affected by the presence of large number of ions, each CH3COO− group binds about 6.23 ± 2.01 to 7.35 ± 1.73 water molecules, which indicates a relatively strong interaction between CH3COO− and water molecules. The larger uncertainty of the CN of Na+ and OC(OOC) reflects the relative looseness of Na-OC and Na-OOC ion pairs in aq. NaOAc solutions, even at the highest concentration (4.453 mol/L), suggesting the lack of contact ion pair (CIP) formation. In aq. NaOAc solutions, the so called “structure breaking” property of Na+ and CH3COO− become effective only for the second hydration sphere of bulk water. The DFT calculations of CH3COONa (H2O)n=5–7 clusters suggest that the solvent-shared ion pair (SIP) structures appear at n = 6 and become dominant at n = 7, which is well consistent with the result from X-ray scattering.

Ker-050, a Novel Inhibitor of Tgfβ Superfamily Signaling, Induces Red Blood Cell Production By Promoting Multiple Stages of Erythroid Differentiation

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 34-34
Author(s):  
Marina Feigenson ◽  
Remya Nathan ◽  
Christopher Materna ◽  
Alana Gudelsky ◽  
Evan Lema ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Single Dose ◽  
Late Stage ◽  
Fold Increase ◽  
Post Treatment ◽  
Publicly Traded ◽  
Post Dose ◽  
Erythroid Precursors ◽  
Multiple Stages ◽  
Tgfβ Superfamily

Diseases such as myelodysplastic syndrome (MDS) and myelofibrosis (MF) are characterized by ineffective hematopoiesis resulting in one or multiple cytopenias. Disease-causing defects occur across multiple cell lineages and stages of hematopoiesis, making development of an effective treatment for all patients challenging. Current treatment options to address anemia in these diseases target discreet stages in erythropoiesis, whereas defects leading to ineffective hematopoiesis can occur throughout the pathway. Therefore, a treatment that more globally modulates hematopoiesis has the potential to treat broad patient groups. The TGFβ superfamily plays a key role in regulating hematopoiesis; as signaling via SMAD2/3 activation results in cell quiescence, inhibiting precursors from progressing through later stages of hematopoiesis. KER-050, a modified ActRIIA ligand trap, promotes hematopoiesis through inhibition of ligands that signal though SMAD2/3, including activins and GDFs. In a Phase 1 clinical study, administration of KER-050 to healthy volunteers led to robust, rapid and sustained increases in red blood cells (RBCs), hemoglobin (HGB) and platelets, supporting an effect on the multiple stages of hematopoiesis. Here, we characterize the time course of KER-050-mediated effects on RBC production and changes in erythroid precursor cell populations in mice to characterize the mechanism of action of KER-050 on erythropoiesis. Mice treated with a single dose of a research form of KER-050 (RKER-050, 10mg/kg) had increased RBCs, HGB and hematocrit (HCT) (+8%, +9%, +7%, respectively) 12 hours after administration compared to vehicle-treated mice (VEH), and this effect was further increased on Day 7. There was also a reduction in the number of enucleated erythroid cells in the bone marrow and a parallel increase in the percent of immature reticulocytes (RET) in peripheral blood, suggesting an increased outflux of RET into circulation. This observation is consistent with RKER-050 promoting the maturation of late stage erythroid precursors leading to increases in RBCs, HGB and HCT as early as 12 hours post treatment and remaining 14 days post a single dose. In studies evaluating the effect of RKER-050 on bone marrow erythroid progenitors, a 2-fold increase in late orthochromatic erythroblasts/RETs (EryC) at Days 2 and 7 post-dose was observed. These data are consistent with RKER-050 promoting maturation and release of late-stage erythroid precursors into circulation. RKER-050 also elicited effects on early progenitors. Day 2 post-dose, there was a 2-fold increase in CFU-Es, with a 46% decrease in poly-erythrochromatic/early orthochromatic erythroid precursors (EryB) at Day 4, as compared to VEH. Day 7 post treatment, both CFU-Es and the EryB population returned to VEH levels. The increase in early progenitors appears to replenish the polychromatic erythroblasts (as shown by the return to VEH level of EryB precursors at Day 7), allowing for continued supply of maturing RETs. Consistent with this hypothesis, RKER-050-mediated changes in erythroid precursors continued to Day 14 with significantly increased early progenitor population (BFU-E +24%) and increased late stage erythroid precursors (EryB +40%, EryC 7-fold) while maintaining increased circulating RETs and RBCs. These data demonstrate that the RKER-050 treatment increases early progenitor cells which continue to mature and contribute to the overall upregulation of erythropoietic tone. Surprisingly, RKER-050 treatment resulted in a greater than 2-fold increase in serum levels of erythropoietin (Epo) at Days 4, 7 and 14. These counterintuitive results demonstrate that RKER-050 promotes erythropoiesis while at the same time increasing Epo. This effect may result in a feed-forward effect on the system and result in a sustained upregulation of erythropoietic tone. Overall, these data demonstrate that KER-050 stimulates terminal maturation of late-stage erythroid precursors, expands the early stage precursor population and progresses precursors through erythropoiesis. Additionally, KER-050 increases Epo within the milieu of elevated RBCs. The ability of KER-050 to target multiple stages along the erythropoiesis cascade makes it an appealing therapeutic candidate for diseases that cause anemia due to ineffective erythropoiesis, including MDS and MF, where defects can arise throughout the erythropoietic pathway. Disclosures Feigenson: Keros Therapeutics: Current Employment. Nathan:Keros Therapeutics: Current Employment. Materna:Keros Therapeutics: Current Employment. Gudelsky:Keros Therapeutics: Current Employment. Lema:Keros Therapeutics: Current Employment, Current equity holder in publicly-traded company. Tseng:Mitobridge: Current equity holder in private company; Keros Therapeutics: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties. Fisher:Keros Therapeutics: Current Employment, Current equity holder in publicly-traded company. Seehra:Keros Therapeutics: Current Employment, Current equity holder in publicly-traded company. Lachey:Keros Therapeutics: Current Employment, Current equity holder in publicly-traded company.

Analytical Methods for Diethylstilbestrol in Feeds and Premixes

1966 ◽  
Vol 49 (5) ◽  
pp. 895-898
Author(s):  
Loyal R Stone
Keyword(s):  
Acetic Acid ◽  
Analytical Methods ◽  
Sodium Acetate ◽  
Buffer System ◽  
Official Method ◽  
Sodium Acetate Solution ◽  
Acetate Solution ◽  
Acid Buffer System ◽  
Acetic Acid Buffer

Abstract Methods are presented in which diethylstilbestrol is extracted from feeds in the Goldfisch apparatus, transferred into alkaline sodium acetate solution to avoid emulsions, and measured colorimetrically in a sodium acetate-acetic acid buffer system. The procedure is rapid, and results agree closely with those obtained by the official method. Procedures are also presented for determination of diethylstilbestrol in molasses and fat mixtures.

The Basis of Bentazon Antagonism on Sethoxydim Absorption and Activity

Weed Science ◽  
1989 ◽  
Vol 37 (3) ◽  
pp. 400-404 ◽  
Author(s):  
Gunawan Wanamarta ◽  
Donald Penner ◽  
James J. Kells
Keyword(s):  
Sodium Salt ◽  
Sodium Acetate ◽  
Tomato Fruit ◽  
Weak Acid ◽  
Antagonistic Effect ◽  
Hydroxyl Group ◽  
Sodium Acetate Solution ◽  
Acetate Solution ◽  
Spray Solution ◽  
Leaf Surfaces

The antagonistic effect of bentazon on sethoxydim adsorption and activity was studied in quackgrass. The diffusion of14C-sethoxydim into and through an isolated tomato fruit cuticle was inhibited in the presence of the sodium salt of bentazon. Bentazon also increased the partitioning of14C-sethoxydim into CH2Cl2and water; however, it decreased partitioning into ethyl acetate. Removal of epicuticular wax from quackgrass leaf surfaces did not prevent the antagonism. Addition of sodium acetate or sodium bicarbonate to the sethoxydim spray solution at 10 mM reduced uptake of14C-sethoxydim by quackgrass similar to the effect of bentazon. Sodium ions in the bentazon formulation appeared responsible for the antagonism by exchanging with the H+of the sethoxydim hydroxyl group to form a more polar sodium salt of sethoxydim. The addition of Li+, K+, Cs+, Ca++, and Mg++cations associated with a weak acid also reduced14C-sethoxydim absorption. Addition of organic acids to the spray solution overcame the antagonism by preventing the formation of sodium salt of sethoxydim. In the field, the addition of a 3000 ppm sodium acetate solution delivering 0.56 kg/ha produced the same antagonism as bentazon on quackgrass control with sethoxydim.

Studies on Iron (Fe[sup 3+]∕Fe[sup 2+])-Complex/Bromine (Br[sub 2]∕Br[sup −]) Redox Flow Cell in Sodium Acetate Solution

2006 ◽  
Vol 153 (5) ◽  
pp. A929 ◽  
Author(s):  
Y. H. Wen ◽  
H. M. Zhang ◽  
P. Qian ◽  
H. T. Zhou ◽  
P. Zhao ◽  
...  
Keyword(s):  
Sodium Acetate ◽  
Flow Cell ◽  
Sodium Acetate Solution ◽  
Acetate Solution ◽  
Redox Flow Cell

Acute treatment of migraine with the selective 5-HT1F receptor agonist lasmiditan – A randomised proof-of-concept trial

Cephalalgia ◽  
2010 ◽  
Vol 30 (10) ◽  
pp. 1170-1178 ◽  
Author(s):  
Michel D Ferrari ◽  
Markus Färkkilä ◽  
Uwe Reuter ◽  
Alison Pilgrim ◽  
Charles Davis ◽  
...  
Keyword(s):  
Adverse Events ◽  
Acute Treatment ◽  
Neural Mechanism ◽  
Dose Finding ◽  
Stopping Rules ◽  
Tolerability Profile ◽  
Proof Of Concept ◽  
Post Dose ◽  
Double Blind ◽  
Clinical Experiments

Introduction: Lasmiditan (COL-144; LY573144) is a novel, highly selective and potent agonist at 5-HT1F receptors that lacks vasoconstrictor activity. Preclinical and early clinical experiments predict acute antimigraine efficacy of COL-144 that is mediated through a non-vascular, primarily neural, mechanism. Subjects and methods: In a randomised, multicentre, placebo-controlled, double-blind, group-sequential, adaptive treatment-assignment, proof-of-concept and dose-finding study, we treated 130 subjects in-hospital during a migraine attack. Subjects were allocated to an intravenous dose level of lasmiditan or placebo in small cohorts. The starting dose was 2.5 mg. Subsequent doses were adjusted, up or down, according to the safety and efficacy seen in the preceding cohort. The primary outcome measure was headache response defined as improvement from moderate or severe headache at baseline to mild or no headache at 2 h post-dose. The study was designed to explore the overall dose response relationship but was not powered to differentiate individual doses from placebo, nor to detect effect differences for other migraine symptoms. Results: Forty-two subjects received placebo and 88 received lasmiditan in doses of 2.5–45 mg. Subjects were observed in the clinic for 4 h after treatment and used a diary card to record symptoms and adverse events for up to 24 h. The study was terminated when the 20 mg dose met predefined efficacy stopping rules. Of subjects treated in the 10, 20, 30 and 45 mg lasmiditan dose groups, 54–75% showed a 2 h headache response, compared to 45% in the placebo group ( P = 0.0126 for the linear association between response rates and dose levels). Patient global impression at 2 h and lack of need for rescue medication also showed statistically significant linear correlations with dose. Lasmiditan was generally well tolerated. Adverse events were reported by 65% of subjects on lasmiditan and by 43% on placebo and were generally mild. Dizziness, paresthesia and sensations of heaviness (usually limb) were more common on lasmiditan. Conclusions: At intravenous doses of 20 mg and higher, lasmiditan proved effective in the acute treatment of migraine. Further studies to assess the optimal oral dose and full efficacy and tolerability profile are under way. The non-vascular, neural mechanism of action of lasmiditan may offer an alternative means to treat migraine especially in patients who have contra-indications for agents with vasoconstrictor activity. The clinicaltrials.gov identifier for this study is NCT00384774.

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