scholarly journals 2,4,6-Tribromophenol Disposition and Kinetics in Rodents: Effects of Dose, Route, Sex, and Species

2019 ◽  
Vol 169 (1) ◽  
pp. 167-179 ◽  
Author(s):  
Gabriel A Knudsen ◽  
Andrew W Trexler ◽  
Alicia C Richards ◽  
Samantha M Hall ◽  
Michael F Hughes ◽  
...  
Keyword(s):  
Oral Dose ◽  
Single Oral Dose ◽  
Ex Vivo ◽  
Systemic Exposure ◽  
Compartment Model ◽  
Repeated Administration ◽  
Environmental Matrices ◽  
Rat Skin ◽  
Sd Rats ◽  
Two Compartment Model

Abstract 2,4,6-tribromophenol (TBP, CAS No. 118-79-6) is widely used as a brominated flame retardant and wood antifungal agent. TBP is frequently detected in environmental matrices, biota, and humans. In female SD rats, systemically available TBP (10 µmol/kg, IV) was rapidly excreted primarily via urine, with approximately 61% of the dose recovered after 4 h, and 89%–94% in 24 h; 5% was recovered in feces; and 1%–2% in blood/tissues. TBP administered to female SD rats (0.1–1000 µmol/kg) by gavage was well absorbed, with approximately 25% eliminated via urine after 4 h and approximately 88% after 24 h. Approximately 11% of a single oral dose was recovered in bile. Male SD rats and B6C3F1/J mice of both sexes had similar disposition profiles when administered a single oral dose of TBP (10 µmol/kg). Following administration, fecal recoveries varied only slightly by dose, sex, or species. TBP readily passed unchanged through both human (ex vivo only) and rat skin with between 55% and 85% of a 100 nmol/cm2 passing into or through skin. Concentrations of TBP in blood fit a two-compartment model after IV-dosing and a one-compartment model after oral dosing. Urine contained a mixture of TBP, TBP-glucuronide, and TBP-sulfate. Fecal extracts contained only parent TBP whereas bile contained only TBP-glucuronide. TBP did not appear to bioaccumulate or alter its own metabolism after repeated administration. TBP was readily absorbed at all doses and routes tested with an oral bioavailability of 23%–27%; 49% of TBP is expected to be dermally bioavailable in humans. From these data, we conclude that humans are likely to have significant systemic exposure when TBP is ingested or dermal exposure occurs.

scholarly journals Effect of single oral dose of azithromycin, clarithromycin, and roxithromycin on polymorphonuclear leukocyte function assessed ex vivo by flow cytometry.

1996 ◽  
Vol 40 (9) ◽  
pp. 2039-2042 ◽  
Author(s):  
C Wenisch ◽  
B Parschalk ◽  
K Zedtwitz-Liebenstein ◽  
A Weihs ◽  
I el Menyawi ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Oral Dose ◽  
Single Oral Dose ◽  
Ex Vivo ◽  
Reactive Oxygen ◽  
Fluorescein Isothiocyanate ◽  
Neutrophil Granulocytes ◽  
Oxygen Production ◽  
Phagocytic Cells ◽  
Phagocytic Capacity

Azithromycin was given as a single oral dose (20 mg/kg of body weight) to 12 volunteers in a crossover study with roxithromycin (8 to 12 mg/kg) and clarithromycin (8 to 12 mg/kg). Flow cytometry was used to study the phagocytic functions and the release of reactive oxygen products following phagocytosis by neutrophil granulocytes prior to administration of the three drugs, 16 h after azithromycin administration, and 3 h after clarithromycin and roxithromycin administration. Phagocytic capacity was assessed by measuring the uptake of fluorescein isothiocyanate-labeled bacteria. Reactive oxygen generation after phagocytosis of unlabeled bacteria was estimated by the amount of dihydrorhodamine 123 converted to rhodamine 123 intracellularly. Azithromycin resulted in decreased capacities of the cells to phagocytize Escherichia coli (median [range], 62% [27 to 91%] of the control values; P < 0.01) and generate reactive oxygen products (75% [34 to 26%] of the control values; P < 0.01). Clarithromycin resulted in reduced phagocytosis (82% [75 to 98%] of control values; P < 0.01) but did not alter reactive oxygen production (84% [63 to 113%] of the control values; P > 0.05). Roxithromycin treatment did not affect granulocyte phagocytosis (92% [62 to 118%] of the control values; P > 0.05) or reactive oxygen production (94% [66 to 128%] of the control value; P > 0.05). No relation between intra- and/or extracellular concentrations of azithromycin and/or roxithromycin and the polymorphonuclear phagocyte function and/or reactive oxygen production existed (P > 0.05 for all comparisons). These results demonstrate that the accumulation of macrolides in neutrophils can suppress the response of phagocytic cells to bacterial pathogens after a therapeutic dose.

Escalating systemic exposure of continuous infusion topotecan in children with recurrent acute leukemia.

1996 ◽  
Vol 14 (5) ◽  
pp. 1504-1511 ◽  
Author(s):  
W L Furman ◽  
S D Baker ◽  
C B Pratt ◽  
G K Rivera ◽  
W E Evans ◽  
...  
Keyword(s):  
Acute Leukemia ◽  
Continuous Infusion ◽  
Severe Combined Immunodeficiency ◽  
Systemic Exposure ◽  
Compartment Model ◽  
Complete Response ◽  
Bayesian Algorithm ◽  
Two Compartment Model ◽  
Scid Mouse Model

PURPOSE To determine the maximum-tolerated systemic exposure (MTSE) and exposure-limiting toxicity of continuous infusion topotecan in children with recurrent acute leukemia. PATIENTS AND METHODS Patients received escalating levels of topotecan systemic exposure as measured by steady-state topotecan lactone concentration (Css). Samples obtained within the first 24 hours were measured by high-pressure liquid chromatography (HPLC) for topotecan. A two-compartment model was fit to the data using a Bayesian algorithm. Css was calculated for each patient; if it differed by more than 20% of target, a new dosage was begun within 6 hours. Follow-up concentrations were obtained as well as serial plasma samples postinfusion. Toxicity and evidence of activity were assessed after each course. RESULTS Thirteen boys and five girls received 23 courses of topotecan. Target Css ranged from 1.0 to 5.3 ng/mL (topotecan doses, 0.5 to 3.3 mg/m2/d). Nineteen of 23 courses were within +/- 20% of target after adjustment (range, 77% to 139%). The MTSE was 4.0 ng/mL, and mucositis was exposure-limiting at 5.3 ng/mL. A significant relation between topotecan lactone Css and the severity of mucositis was observed. Myelosuppression was experienced but was not considered exposure-limiting. One complete response and one partial response were noted. CONCLUSION The MTSE for continuous infusion topotecan was 4.0 ng/mL. Responses were noted at Css comparable to those producing responses in a severe combined immunodeficiency (SCID) mouse model. Further studies of topotecan are warranted.

Single Dose Administration of rFVIIa and NN1731 in Two Hemophilia A Dogs.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3144-3144 ◽  
Author(s):  
Mirella Ezban ◽  
Lone Frost ◽  
Dorthe Viuff ◽  
Judi Møss ◽  
Mark Kloos ◽  
...  
Keyword(s):  
Hemophilia A ◽  
Ex Vivo ◽  
Compartment Model ◽  
Initial Distribution ◽  
Coagulation Assays ◽  
Two Compartment Model ◽  
Dose Study ◽  
Related Proteins

Abstract Introduction: The objective of this pilot study was to evaluate and compare the pharmacokinetic and pharmacodynamic (PK/PD) profile of rFVIIa and NN1731 in two hemophilia A dogs. In addition, it was the aim to evaluate the use of TEG for monitoring rFVIIa/NN1731 activity after in vivo administration and to compare with ex vivo spiking data from a previous study. NN1731 is a new rFVIIa analoge with enhanced activity (Allen et al. Arterioscler. Thromb. Vasc. Biol.2007;27:683–689). In hemophilia patients as well as hemophilia dogs the clot formation is impaired and reflected in coagulation assays such as thromboelastography (TEG) and APTT. The choice of hemophilia dogs is based upon the knowledge that the pharmacokinetics of human coagulations factors (FVIII, FIX and rFVIIa) as well as the effective dose is similar to that in humans. In normal dogs, it is not possible to evaluate the effect of these procoagulant proteins in coagulation assays as no impaired clotting is observed. Methods: rFVIIa and NN1731 (280 μg/kg IV) were administered to two hemophilia dogs on separate days and plasma samples collected at different time points. FVIIa activity was measured by the FVIIa clot assay and values were used for pharmacokinetic assessment. The same pharmacokinetic models, a non-compartmental method and a two compartment model, respectively, were used as was the case in the First Human Dosing (FHD) trial of NN1731 (NN1731–1639). Analysis of PD markers in dogs included: APTT, PT and whole blood thromboelastography analysis, recently developed for use in hemophilia dogs. Results: Based on the FVIIa activity profile in the two dogs it was observed that the values obtained at the first time point (C5 min), were higher after treatment with NN1731 than after rFVIIa. All activity based assays including TEG demonstrated that NN1731 was cleared faster than rFVIIa., FVIIa activity (FVIIa clot assay), showed a rapid initial distribution and/or elimination of FVIIa activity (t1/2α:0.3 h) followed by a less rapid elimination phase (t½β:3.5 h). Similar profile and values were obtained for NN1731 in the FHD dose study (J. Møss et al, ISTH, 2007) Conclusions: This study indicates that in hemophilia A dogs, NN1731 and rFVIIa have distinct PK profiles and very similar to what is observed in man. All activity assays show the same qualitative profile, the FVIIa clot assay being the most sensitive assay. The TEG data obtained in vivo are in accordance with the values obtained after in vitro spiking. The data support the use of hemophilia dogs for evaluating the pharmacokinetic and pharmacodynamic profiles of FVIIa related proteins.

Single oral dose of maraviroc does not prevent ex-vivo HIV infection of rectal mucosa in HIV-1 negative human volunteers

AIDS ◽  
2015 ◽  
Vol 29 (16) ◽  
pp. 2149-2154 ◽  
Author(s):  
Josep Coll ◽  
José Moltó ◽  
Jaume Boix ◽  
Elisabet Gómez-Mora ◽  
Laura Else ◽  
...  
Keyword(s):  
Oral Dose ◽  
Hiv Infection ◽  
Single Oral Dose ◽  
Ex Vivo ◽  
Rectal Mucosa ◽  
Human Volunteers ◽  
Hiv 1

scholarly journals Thalidomide Inhibits Granulocyte Responses in Healthy Humans after Ex Vivo Stimulation with Bacterial Antigens

2001 ◽  
Vol 45 (5) ◽  
pp. 1547-1549 ◽  
Author(s):  
Nicole P. Juffermans ◽  
Annelies Verbon ◽  
Marc J. Schultz ◽  
C. Erik Hack ◽  
Sander J. H. van Deventer ◽  
...  
Keyword(s):  
Oral Dose ◽  
Single Oral Dose ◽  
Ex Vivo ◽  
Lipoteichoic Acid ◽  
Neutrophil Activation ◽  
Activation Marker ◽  
Healthy Humans ◽  
Bacterial Antigens

ABSTRACT Ingestion of thalidomide was associated with a reduction in the upregulation of the granulocyte activation marker CD11b and a reduced capacity to release elastase and lactoferrin after stimulation with lipopolysaccharide or lipoteichoic acid. A single oral dose of thalidomide attenuates neutrophil activation upon ex vivo stimulation with bacterial antigens.

scholarly journals Effects of ibogaine per os application on redox homeostasis in rat liver and erythrocytes

2019 ◽  
Vol 71 (1) ◽  
pp. 133-144
Author(s):  
Teodora Vidonja-Uzelac ◽  
Nikola Tatalovic ◽  
Milica Mijovic ◽  
Gordana Kozelj ◽  
Aleksandra Nikolic-Kokic ◽  
...  
Keyword(s):  
Body Weight ◽  
Oral Dose ◽  
Single Oral Dose ◽  
Rat Liver ◽  
Ex Vivo ◽  
Redox Homeostasis ◽  
Antioxidant Enzyme Activities ◽  
Glutathione S Transferase ◽  
Cellular Energy ◽  
Species Production

Ibogaine, administered as a single oral dose (1-25 mg/kg body weight), has been used as an addiction-interrupting agent. Its effects persist for up to 72 h. Ex vivo results showed that ibogaine induced cellular energy consumption and restitution, followed by increased reactive oxygen species production and antioxidant activity. Therefore, the aim of this work was to explore the effect of a single oral dose of ibogaine (1 or 20 mg/kg body weight) on antioxidative defenses in rat liver and erythrocytes. Six and 24 h after ibogaine administration, histological examination showed glycogenolytic activity in hepatocytes, which was highest after 24 h in animals that received 20 mg/kg ibogaine. There were no changes in the activities of superoxide dismutases, catalase, glutathione peroxidase, glutathione reductase and glutathione-S-transferase in the liver and erythrocytes after ibogaine treatment, regardless of the dose. Hepatic xanthine oxidase activity was elevated in rats that received 20 mg/kg compared to the controls (p<0.01), suggesting faster adenosine turnover. TBARS concentration was elevated in the group treated with 1 mg/kg after 24 h compared to the controls (p<0.01), suggesting mild oxidative stress. Our results show that ibogaine treatment influenced hepatic redox homeostasis, but not sufficiently to remodel antioxidant enzyme activities at 6 and 24 h post-ibogaine application.

Design, Synthesis and Biological Evaluation of Camptothecin Conjugated with NSAIDs as Novel Dual-actin Antitumor Agents

2019 ◽  
Vol 16 (12) ◽  
pp. 1378-1386
Author(s):  
Xingchen Cai ◽  
Weiwei Huang ◽  
Yi Huang ◽  
Lihua Xia ◽  
Miao Liu ◽  
...  
Keyword(s):  
Oral Dose ◽  
Single Oral Dose ◽  
Human Plasma ◽  
Biological Evaluation ◽  
Effective Control ◽  
Synergistic Activity ◽  
Sd Rats ◽  
Anti Cancer ◽  
Cancer Activity

Objective: The single-agent therapy was unable to provide an effective control of the malignant process, a well-established strategy to improve the efficacy of antitumor therapy is the rational design of drug combinations aimed at achieving synergistic effects. Objective: The objective of this study is generating the new potential anticancer agents with synergistic activity. Owing to the unique mechanism of action of Camptothecin (CPT), it has shown abroad spectrum of anti-cancer activity against human malignancies, and growing evidence revealed that Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) reduce the risk of different kinds of cancers. So four CPT-NSAIDs conjugates were synthesized and evaluated. Methods: In this study, a series of novel CPT - NSAIDs derivatives were synthesized by esterification. These new compounds were evaluated for in vitro antitumor activity against tumor cell lines A549, Hela, HepG2, HCT116 by MTT assay. To probe the required stabilities as prodrugs, stability tests were studied in human plasma. To further evaluate the stability of Ketoprofen-CPT in vivo, the female SD rats were used to determine the pharmacokinetics following a single oral dose. Results: In vitro results showed that Ketoprofen-CPT and Naproxen-CPT conjugates possessed nice efficacy. In a molecular docking model, the two conjugates interacted with Topo I-DNA through hydrogen bonds, <pi>-<pi> stacking and so on.In human plasma results showed that the prodrug was converted to ketoprofen and another compound. The female SD rats were used to determine the pharmacokinetics following a single oral dose, the half-life (t1/2) of Ketoprofen-CPT was approximately 12 h which was much longer than that of CPT. Conclusion: Good activity was noted for some compounds will be helpful for the design of dualaction agents with most promising anti-cancer activity.

scholarly journals Acute and 28-days subacute toxicity studies of Gαq-RGS2 signaling inhibitor

2021 ◽  
Vol 37 (1) ◽  
Author(s):  
Jayesh V. Beladiya ◽  
Anita A. Mehta
Keyword(s):  
Body Weight ◽  
Oral Dose ◽  
Oral Administration ◽  
Single Oral Dose ◽  
Hematological Parameters ◽  
Weight Ratio ◽  
Repeated Administration ◽  
Organ Damage ◽  
Synthetic Compound ◽  
Single Oral Administration

Abstract Background The aim of study was to evaluate the single oral dose and 28 day repeated oral administration toxicity profile of the synthetic compound Gαq-RGS2 signaling inhibitor, (1-(5-chloro-2-hydroxyphenyl)-3-(4-(trifluoromethyl)phenyl)-1 H-1,2,4-triazol-5(4 H)-one) as per OECD guideline 425 (2008a) and 407 (2008b), respectively. Results In acute toxicity study, a single oral dose administration of Gαq-RGS2 signaling inhibitor did not show any mortality at doses of 5, 50, 300 and 2000 mg/kg within 24 h and 14 days. The treatment of Gαq-RGS2 signaling inhibitor at dose 10 and 100 mg/kg for 28 days did not show any mortality, significant changes in the increase of body weight, various organ damage markers, hematological parameters, relative organ/body weight ratio and microscopic anatomical texture of essential organs as compared to vehicle and normal control. Conclusions A single oral administration of Gαq-RGS2 signaling inhibitor up to dose of 2000 mg/kg in mice and repeated administration of Gαq-RGS2 signaling inhibitor at higher dose 100 mg/kg for 28 days in the rats is safe.

Failure of Salicylate to Reduce Inhibition of Human Venous Prostacyclin in Synthesis by Conventional Dose Aspirin

1983 ◽  
Vol 49 (01) ◽  
pp. 051-052 ◽  
Author(s):  
S P Hanley ◽  
J Hughes
Keyword(s):  
Oral Dose ◽  
Single Oral Dose ◽  
Sodium Salicylate ◽  
Ex Vivo ◽  
Inhibitory Effect ◽  
Conventional Dose ◽  
Dose Aspirin ◽  
Prostacyclin Synthesis

SummaryEx vivo venous prostacyclin synthesis was measured in 24 patients who received no medication, or a single oral dose of aspirin 300 mg, sodium salicylate, 500 mg, or a combination of sodium salicylate 500 mg followed by aspirin 300 mg 1 1/2 or 3 hr later. Aspirin alone substantially reduced PGI2 synthesis but sodium salicylate alone had no effect. Sodium salicylate administration prior to aspirin did not reverse the inhibitory effect of aspirin on PGI2 synthesis.

Sign in / Sign up

Export Citation Format

Share Document