Detection of cocaine and its metabolites in whole blood and plasma following a single dose, controlled administration of intranasal cocaine

2019 ◽  
Vol 11 (9) ◽  
pp. 1419-1430 ◽  
Author(s):  
Eleanor L. Menzies ◽  
John R.H. Archer ◽  
Paul I. Dargan ◽  
Mark C. Parkin ◽  
Takahiro Yamamoto ◽  
...  
Keyword(s):  
Single Dose ◽  
Whole Blood ◽  
Intranasal Cocaine

Suppression of endotoxin-inducible cytokines in whole blood from human subjects following single dose of recombinant human interleukin-11

1999 ◽  
Vol 5 (4) ◽  
pp. 197-204
Author(s):  
L.L. Reznikov ◽  
A.J. Puren ◽  
G. Fantuzzi ◽  
G.R. Hamner ◽  
U.S. Schwertschlag ◽  
...  
Keyword(s):  
Single Dose ◽  
Whole Blood ◽  
Human Subjects ◽  
Interleukin 11

Clinical Pharmacokinetics of CAL-101, a p110δ Isoform-Selective PI3K Inhibitor, Following Single- and Multiple-Dose Administration In Healthy Volunteers and Patients with Hematological Malignancies

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1774-1774 ◽  
Author(s):  
Heather K Webb ◽  
Hao Chen ◽  
Albert S Yu ◽  
Sissy Peterman ◽  
Leanne Holes ◽  
...  
Keyword(s):  
Single Dose ◽  
Healthy Volunteers ◽  
Total Dose ◽  
Whole Blood ◽  
Multiple Dose ◽  
Pi3k Pathway ◽  
Preliminary Evaluation ◽  
Clinical Pharmacokinetics ◽  
Lymphoid Malignancies ◽  
Dose Levels

Abstract Abstract 1774 Phosphatidylinositol 3-kinases (PI3Ks) regulate several cellular functions including motility, proliferation, and survival. PI3K pathway signaling is mediated by the Class I PI3K isoforms, α, β, δ and γ. The PI3K p110δ isoform is preferentially expressed in cells of hematological origin and in a variety of malignant cells. CAL-101 is a potent p110δ inhibitor with an EC50 of 62 nM in a whole-blood p110δ assay and >200-fold selectivity for p110δ relative to other PI3K isoforms. Consistent with this target selectivity, nonclinical toxicology and safety pharmacology data supported initial clinical assessment of oral CAL-101 in single-dose, multiple-dose, and food-effect studies in healthy volunteers. Because CAL-101 is a CYP450 3A4 substrate, the effect of ketoconazole (a potent CYP450 3A4 inhibitor) on CAL-101 pharmacokinetics was also evaluated in healthy volunteers. Preliminary evaluation of disposition, metabolism and elimination in healthy volunteers was achieved by coadministering a trace amount of [14C]CAL-101 and unlabeled CAL-101 either orally or intravenously (IV) with samples evaluated by accelerator mass spectrometry. CAL-101 pharmacokinetics (PK) were subsequently evaluated in patients with lymphoid malignancies. In healthy volunteers, CAL-101 was well tolerated at 400 mg (the highest single dose tested) and at 200 mg BID through 7 days (the highest multiple dose tested). The drug has also been symptomatically well tolerated in patients with lymphoid malignancies receiving CAL-101 at dose levels through 350 mg/kg (the highest dose tested) over many months. Monitorable, reversible transaminase elevations have been observed in some patients, most commonly in patients with lymphoma. No maximum tolerated dose (MTD) has been apparent. Increases in Cmax and AUC are less than dose proportional, revealing minimal gains in plasma exposure at dose levels >150 mg BID. The mean volume of distribution was moderate at 57.7 L. The t1/2 was ∼8 hours across all dose levels and there was no plasma accumulation over 7 or 28 days. The collective data support BID dosing at ≥150 mg; dose levels in this range maintain steady-state trough plasma concentrations that are >10-fold above the EC50 for the in vitro whole-blood assay. [14C]CAL-101 was metabolized to only 1 metabolite in plasma and CAL-101-derived materials were primarily excreted in feces (>65% of total dose) with minimal elimination via urine (<15% of total dose). A high-fat, high-calorie meal had no effect on Cmax but slowed absorption, leading to a shift in observed median Tmax from 1.5 h to 4.5 h, and a moderate 1.4-fold increase in AUC; these data suggest that CAL-101 can be given with or without food. When administered following 4 days of ketoconazole, increases in mean CAL-101 Cmax and AUC values were 1.3- and 1.8-fold, respectively; thus, CAL-101 is not a sensitive substrate for CYP450 3A4 and coadministration of CAL-101 with CYP450 3A4 inhibitors does not appear to be contraindicated. Taken together with clinical data documenting PI3K pathway inhibition, modulation of chemokine signaling, and substantial dose-dependent antitumor activity, these findings provide a characterization of CAL-101 clinical pharmacology that supports CAL-101 development as an investigational therapy for cancer and other indications. Disclosures: Webb: Calistoga Pharmaceuticals: Employment. Chen:Calistoga Pharmaceuticals: Employment. Yu:Calistoga Pharmaceuticals: Employment. Peterman:Calistoga Pharmaceuticals: Employment. Holes:Calistoga Pharmaceuticals: Employment. Lannutti:Calistoga Pharmaceutical Inc.: Employment. Miller:Calistoga Pharmaceuticals: Employment. Ulrich:Calistoga Pharmaceuticals: Employment, Equity Ownership.

Suppression of endotoxin-inducible cytokines in whole blood from human subjects following single dose of recombinant human interleukin-11

1999 ◽  
Vol 5 (4) ◽  
pp. 197-204 ◽  
Author(s):  
Leonid L. Reznikov ◽  
Adrian J. Puren ◽  
Giamila Fantuzzi ◽  
Gary R. Hamner ◽  
Ullrich S. Schwertschlag ◽  
...  
Keyword(s):  
Single Dose ◽  
Whole Blood ◽  
Human Subjects ◽  
Interleukin 11

scholarly journals 1122. Effect of Aluminum Hydroxide/Magnesium Hydroxide/Simethicone and Omeprazole on the Pharmacokinetics of Tebipenem Pivoxil Hydrobromide (TBP-PI-HBr) in Healthy Adult Subjects

2021 ◽  
Vol 8 (Supplement_1) ◽  
pp. S652-S653
Author(s):  
Vipul K Gupta ◽  
Gina Patel ◽  
Leanne Gasink ◽  
Floni Bajraktari ◽  
Yang Lei ◽  
...  
Keyword(s):  
Single Dose ◽  
Oral Dose ◽  
Single Oral Dose ◽  
Aluminum Hydroxide ◽  
Magnesium Hydroxide ◽  
Whole Blood ◽  
Drug Product ◽  
Geometric Mean ◽  
Tebipenem Pivoxil ◽  
Tract Infections

Abstract Background Tebipenem pivoxil hydrobromide (TBP-PI-HBr) is an oral prodrug that is converted to tebipenem (TBP), the active moiety being developed for treating complication urinary tract infections. Antacids and proton pump inhibitors are known to change gastric pH after administration, which could affect the absorption of oral medications. This study evaluated the effect of a single dose of aluminum hydroxide/magnesium hydroxide/simethicone and the effect of multiple doses of omeprazole on the PK of TBP, following a single dose of TBP-PI-HBr. Methods This was an open-label, 3-period, fixed sequence drug-drug interaction study. On Day 1, Period 1, subjects received a single oral dose of TBP-PI-HBr 600 mg (2 x 300 mg tablets) at Hour 0. On Day 1, Period 2, subjects received a single oral 20 mL dose of aluminum hydroxide 800 mg/magnesium hydroxide 800 mg/simethicone 80 mg suspension per 10 mL (Maalox® Advanced Maximum Strength oral suspension) with a single oral dose of TBP-PI-HBr 600 mg at Hour 0. In Period 3, on Days 1 through 5, subjects received a single oral dose of omeprazole 40 mg (Prilosec®) once daily (QD), at Hour -2. On Day 5, a single oral dose of 600 mg TBP-PI-HBr was administered at Hour 0. Whole blood sampling for TBP PK occurred pre-dose and up to 24 hours post dose. Whole blood samples were assayed for TBP by liquid chromatography-tandem mass spectrometry. Results Twenty subject were enrolled and completed the study. Geometric mean ratios for AUC indicated mean TBP exposure (AUC) was approximately 11% lower and mean Cmax was 22% lower for TBP-PI-HBr combined with aluminum hydroxide/magnesium hydroxide/simethicone vs. TBP-PI-HBr alone (Figure). Similarly, geometric mean ratios for AUC indicated mean TBP exposure (AUC) was approximately 11% lower and mean Cmax was 43% lower for TBP-PI-HBr in combination with omeprazole vs. TBP-PI-HBr alone. Because the PK/PD driver for TBP efficacy is AUC dependent, concomitant administration is not expected to impact the efficacy of oral TBP-PI-HBr. Figure 1. Arithmetic mean plasma TBP concentrations following a 600 mg dose of clinical study drug product (A1 and A2) and registrational drug product (B) – PK population. Conclusion Administration of TBP-PI-HBr combined with aluminum hydroxide/magnesium hydroxide/simethicone or omeprazole QD had no meaningful effect on plasma TBP exposure; Cmax decreased with both agents. Co-administration was generally safe and well tolerated. Disclosures Vipul K. Gupta, Ph.D., Spero Therapeutics (Employee, Shareholder) Gina Patel, PhD, Spero Therapeutics, Inc. (Consultant) Leanne Gasink, MD, Spero Therapeutics, Inc. (Consultant) Floni Bajraktari, MSc, Spero Therapeutics, Inc. (Employee) Yang Lei, PhD, Spero Therapeutics, Inc. (Employee) Akash Jain, PhD, Spero Therapeutics, Inc. (Employee) Praveen Srivastava, MS, BS, Spero Therapeutics, Inc. (Employee) Angela Talley, MD, Spero Therapeutics, Inc. (Employee)

AG-348 Activation of Pyruvate Kinase in Vivo Enhances Red Cell Glycolysis in Mice

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4010-4010
Author(s):  
Charles Kung ◽  
Collin Hill ◽  
Yue Chen ◽  
Abhishek Jha ◽  
Penelope Kosinski ◽  
...  
Keyword(s):  
Single Dose ◽  
Pyruvate Kinase ◽  
Whole Blood ◽  
Red Cells ◽  
Red Cell ◽  
Atp Levels ◽  
Glycolytic Activity ◽  
Label Incorporation ◽  
2,3 Dpg

Abstract Pyruvate kinase deficiency (PKD) is an autosomal recessive enzymopathy that is the most common cause of hereditary nonspherocytic hemolytic anemia (HNSHA). PKD is a rare disease characterized by a life-long chronic hemolysis with severe co-morbidities. It is hypothesized that insufficient energy production to maintain red cell membrane homeostasis promotes the chronic hemolysis. Treatment is generally palliative, focusing on the resultant anemia, and there are no approved drugs that directly target mutated pyruvate kinase. AG-348 is an allosteric activator of the red cell isoform of pyruvate kinase (PKR) that has recently entered Phase I clinical trials in normal healthy volunteers. AG-348 increases the catalytic efficiency and enhances the protein stability of a spectrum of recombinantly expressed PKR mutant proteins that have been associated with PKD. PKD red cells are characterized by changes in metabolism associated with defective glycolysis, including a build-up of the upstream glycolytic intermediate 2,3-DPG and deficiency in the PKR product adenosine triphosphate (ATP). PKR flux, e.g. the rate of carbon flow through the PKR enzyme reaction, was examined in PKD patient or wild type (WT) donor blood samples by incubation of whole blood with a stable isotope tracer, [U-13C6]-glucose. At various time points after the addition of [U-13C6]-glucose, metabolism was quenched and metabolites were extracted. Metabolite pool sizes and 13C label incorporation into glycolytic intermediates were monitored by LC/MS. The rate of label incorporation was found to be significantly slower in PKD patient red cells, consistent with decreased glycolytic activity. Treatment of PKD red cells with AG-348 ex-vivo induces changes in metabolism consistent with increased glycolytic activity including reduced 2,3-DPG levels, increased ATP levels, and increased PKR enzyme activity levels. The effect of AG-348 on red cell metabolism in vivo was evaluated in mice. C57/BL6 mice were dosed by oral gavage either with a single dose, or with multiple doses (BID) of AG-348 for 7 days. Dose levels tested were 1 mpk, 10 mpk, 50 mpk, and 150 mpk. Following the last dose, mice were bled to evaluate drug exposure and pharmacodynamic markers including 2,3-DPG and ATP levels, and PKR activity. AG-348 was demonstrated to be a well-behaved compound, with dose-proportional increase in exposure, both in the single-dose and multiple dose studies. A single dose of AG-348 resulted in a dose-dependent increase in PKR activity levels, concomitant with reduction in 2,3-DPG levels. There were no significant changes in ATP levels after a single administration of AG-348. In the multiple-dose studies, similar changes in PKR activity and 2,3-DPG levels were observed. In contrast to the single-dose study, ATP levels were observed to be robustly increased in a dose-dependent manner. The effect of AG-348 on PKR flux was assessed in whole blood from mice treated with AG-348. C57BL/6 mice were dosed by oral gavage with AG-348 (150 mg/kg twice daily [BID]) for 3 days. Whole blood was incubated with [U-13C6]-glucose and the metabolite pool sizes and rate of 13C label incorporation into glycolytic intermediates were assessed. The data were subsequently analyzed using a mathematical model to quantify flux through the PKR reaction and it was determined that AG-348 treatment significantly increased flux through the PKR reaction. Collectively, these data demonstrate that AG-348 not only potently binds to and activates the PKR enzyme in vivo, but this enzyme activation induces enhanced glycolytic pathway activity in red cells that results in profound changes in cellular metabolism, as reflected in dramatically increased ATP levels and reduced 2,3-DPG levels. As AG-348 has similar potency against the WT PKR enzyme as against tested mutant PKR enzymes in vitro, these data support the hypothesis that AG-348 treatment may similarly enhance glycolytic activity in PKD patients and thus correct the underlying pathology of PKD. Figure 1 Figure 1. Disclosures Kung: Agios Pharmaceuticals: Employment, Stockholder Other. Hill:Agios Pharmaceuticals: Employment, Stockholder Other. Chen:Agios Pharmaceuticals: Employment, Stockholder Other. Jha:Agios Pharmaceuticals: Employment, Stockholder Other. Kosinski:Agios Pharmaceuticals: Employment, Stockholder Other. Clasquin:Agios Pharmaceuticals: Employment, Stockholder Other. Si:Agios Pharmaceuticals: Employment, Stockholder Other. Kim:Agios Pharmaceuticals: Employment, Stockholder Other. Hixon:Agios Pharmaceuticals: Employment, Stockholder Other. Dang:A: Employment, Stockholder Other. Agresta:Agios Pharmaceuticals: Employment, Stockholder Other. Silverman:Agios Pharmaceuticals: Employment, Stockholder Other. Yang:Agios Pharmaceuticals: Employment, Stockholder Other.

Whole-Blood Single-Dose Kinetics of Chloroquine and Desethylchloroquine in Africans

1986 ◽  
Vol 8 (2) ◽  
pp. 195-199 ◽  
Author(s):  
K. K. Adjepon-Yamoah ◽  
D. Ofori-Adjei ◽  
N. M. Woolhouse ◽  
B. Lindström
Keyword(s):  
Single Dose ◽  
Whole Blood ◽  
Kinetics Of

Vascular atherosclerotic disease: evaluation of the whole-blood f ilterability and red cell membrane microrheological pattern after intravenous administration of a single dose of pentoxifylline

1990 ◽  
Vol 12 (4) ◽  
pp. 263-267 ◽  
Author(s):  
Gregorio Caimi ◽  
Antonio Serra ◽  
Giuseppe Francavilla ◽  
Adele Romano ◽  
Anna Catania ◽  
...  
Keyword(s):  
Single Dose ◽  
Cell Membrane ◽  
Intravenous Administration ◽  
Whole Blood ◽  
Atherosclerotic Disease ◽  
Red Cell ◽  
Red Cell Membrane

THE EFFECTS OF ADRENALECTOMY AND CORTISONE ON ZINC METABOLISM IN THE SEX GLANDS AND ADRENAL OF THE MALE RAT

1960 ◽  
Vol 38 (1) ◽  
pp. 845-851 ◽  
Author(s):  
Allan D. Rudzik ◽  
Bernard E. Riedel
Keyword(s):  
Single Dose ◽  
Adrenal Gland ◽  
Whole Blood ◽  
Zinc Concentration ◽  
Chronic Administration ◽  
Daily Treatment ◽  
Male Rat ◽  
Zinc Metabolism ◽  
Daily Dose ◽  
Zinc Concentrations

The effects of adrenalectomy and of cortisone treatment on the uptake of Zn65 and the concentration of zinc were observed in whole blood, adrenals, testis, and dorsolateral and ventral prostates of the rat. Cortisone was administered to both normal and adrenalectomized animals either as a single dose or as a daily dose over a period of 14 days. Zinc concentration was decreased in adrenalectomized animals in the blood and dorsolateral prostate. The incorporation of Zn65 was decreased after adrenalectomy in the testis and dorsolateral prostate. Daily treatment with cortisone resulted in recovery to normal of the zinc concentrations and uptake of Zn65.The adrenal gland was found to contain a relatively large amount of zinc and this concentration was doubled with the chronic administration of cortisone. A single dose of cortisone had no effect on the concentration of zinc but caused an increase in the uptake of Zn65 in the adrenal.

THE EFFECTS OF ADRENALECTOMY AND CORTISONE ON ZINC METABOLISM IN THE SEX GLANDS AND ADRENAL OF THE MALE RAT

1960 ◽  
Vol 38 (8) ◽  
pp. 845-851 ◽  
Author(s):  
Allan D. Rudzik ◽  
Bernard E. Riedel
Keyword(s):  
Single Dose ◽  
Adrenal Gland ◽  
Whole Blood ◽  
Zinc Concentration ◽  
Chronic Administration ◽  
Daily Treatment ◽  
Male Rat ◽  
Zinc Metabolism ◽  
Daily Dose ◽  
Zinc Concentrations

The effects of adrenalectomy and of cortisone treatment on the uptake of Zn65 and the concentration of zinc were observed in whole blood, adrenals, testis, and dorsolateral and ventral prostates of the rat. Cortisone was administered to both normal and adrenalectomized animals either as a single dose or as a daily dose over a period of 14 days. Zinc concentration was decreased in adrenalectomized animals in the blood and dorsolateral prostate. The incorporation of Zn65 was decreased after adrenalectomy in the testis and dorsolateral prostate. Daily treatment with cortisone resulted in recovery to normal of the zinc concentrations and uptake of Zn65.The adrenal gland was found to contain a relatively large amount of zinc and this concentration was doubled with the chronic administration of cortisone. A single dose of cortisone had no effect on the concentration of zinc but caused an increase in the uptake of Zn65 in the adrenal.

THE EFFECTS OF HYPOPHYSECTOMY AND ACTH ON ZINC METABOLISM IN THE SEX GLANDS AND ADRENALS OF THE MALE RAT

1960 ◽  
Vol 38 (1) ◽  
pp. 1003-1008
Author(s):  
Allan D. Rudzik ◽  
Bernard E. Riedel
Keyword(s):  
Single Dose ◽  
Adrenal Gland ◽  
Whole Blood ◽  
Marked Decrease ◽  
Specific Activity ◽  
Male Rat ◽  
Zinc Metabolism ◽  
Relative Specific Activity ◽  
Daily Dose

The effects of hypophysectomy and ACTH administration on the uptake of Zn65 and the concentration of zinc were observed in whole blood, testis, adrenals, and dorsolateral and ventral prostates of the male rat. ACTH was administered to both intact and hypophysectomized animals either as a single dose or as a daily dose over a period of 14 days.Hypophysectomy resulted in a marked decrease in the relative specific activity in all tissues studied. The administration of ACTH, as a single dose, had no significant effect, but, as a daily dose over a period of 14 days, caused significant changes in both intact and hypophysectomized animals.The probability of a relation between the adrenal gland and the sex glands is discussed. Further a relation between adrenal activity and zinc metabolism is discussed.

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