scholarly journals The biliary excretion of enterokinase in rats. Studies in normal, chronic ethanol-maintained and cirrhotic rats

1981 ◽  
Vol 198 (2) ◽  
pp. 315-319 ◽  
Author(s):  
D A W Grant ◽  
P A Jones ◽  
J Hermon-Taylor
Keyword(s):  
Carbon Tetrachloride ◽  
Intravenous Administration ◽  
Half Life ◽  
Pancreatic Disease ◽  
Chronic Ethanol ◽  
Hepatic Bile ◽  
Catalytically Active ◽  
Dose Number ◽  
The Mean ◽  
Dose Dependent

The excretion of catalytically active human or pig enterokinase in hepatic bile after intravenous administration to normal rats or rats that had been maintained on 20% (v/v) ethanol for 1 year showed similar kinetics to that described for other serum-derived bile proteins. The half-life in serum was 2.5 min or less, and most of the enzyme was excreted within 45 min of administration. This was maintained when up to six successive doses were given at 90 min intervals. The mean amount excreted per dose was independent of the dose number and varied from 0.8% to 2.1% in the normal animals and 1.2% to 2.0% in the chronic ethanol-maintained animals. When three doses of enzyme were given at 30 min intervals, the total amount of active enterokinase recovered in bile was dose-dependent and was consistently higher in the rats drinking 20% (v/v) ethanol. The serum half-life of enterokinase in rats made cirrhotic by inhalation of carbon tetrachloride vapour was extended to 6 min or more. The amount of active enzyme recovered in bile was at least 50% less than in weight-matched normal rats, and excretion was not complete 2h after intravenous administration. The possible significance of these findings in liver and pancreatic disease is discussed.

Pharmacokinetic Comparison of Intravenous and Oral Chloramphenicol in Patients with Haemophilus in fluenzae Meningitis

PEDIATRICS ◽  
1981 ◽  
Vol 67 (5) ◽  
pp. 656-660
Author(s):  
Ram Yogev ◽  
William M. Kolling ◽  
Tommy Williams
Keyword(s):  
Serum Level ◽  
Oral Administration ◽  
Intravenous Administration ◽  
Half Life ◽  
Peak Serum ◽  
Peak Serum Level ◽  
Wide Range ◽  
Csf Levels ◽  
The Mean ◽  
Intravenous And Oral Administration

The pharmacokinetics of chloramphenicol following intravenous and oral administration were studied in 14 infants with Haemophilus influenzae meningitis. Following five days of treatment with intravenous chloramphenicol (100 mg/kg/day every six hours), oral chloramphenicol was substituted at the same dose. Multiple serum levels of chloramphenicol were determined after an intravenous dose on day 4 and after an oral dose on day 10. CSF levels were measured six hours after intravenous or oral chloramphenicol dose on those days (CSF trough). Following intravenous administration, the mean peak serum level of 15.0 µ/g ml was reached at 45 minutes. In comparison, after oral chloramphenicol in the same dosage, the mean peak serum level of 18.5 µg ml was achieved at two to three hours. The mean serum half-life of the drug (6.5 hours) was significantly longer after oral administration than after intravenous chloramphenicol (4.0 hours) (P .001). The increased serum half-life following orally administered chloramphenicol was occasionally associated with drug accumulation. In addition, mean trough CSF levels were somewhat higher when the patient received oral medication (6.6 µg/ml) compared to intravenous administration (4.2 µ/ml) (P .001). For any treatment regimen for H influenzae meningitis that includes a period of oral chloramphenicol therapy the patient should be hospitalized to ensure compliance. Because of the wide range of individual variation in serum half-life that may result in accumulation, periodic monitoring of serum chloramphenicol levels is also recommended.

scholarly journals THU0054 NKTR-358, A NOVEL IL-2 CONJUGATE, STIMULATES HIGH LEVELS OF REGULATORY T CELLS IN PATIENTS WITH SYSTEMIC LUPUS ERYTHEMATOSUS

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 238.2-239 ◽  
Author(s):  
S. Siddhanti ◽  
C. Fanton ◽  
N. Dixit ◽  
L. Lu ◽  
V. Chindalore ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Healthy Volunteers ◽  
Cd8 T Cells ◽  
Half Life ◽  
Research Support ◽  
Cytokine Levels ◽  
Dose Study ◽  
The Mean ◽  
Dose Dependent

Background:Impaired IL-2 production and dysfunction of regulatory T cells (Tregs) have been identified as key immunological defects leading to the breakdown of immune self-tolerance in SLE. Low-dose IL-2 can expand Tregs, but the effect is limited by a narrow therapeutic window for Treg selectivity. Furthermore, the short half-life of IL-2 necessitates frequent administration. NKTR-358 is a polyethylene glycol (PEG) conjugate of recombinant human IL-2 (aldesleukin sequence) and is differentiated from native IL-2 by its altered binding to the IL-2 receptor and prolonged biological activity. NKTR-358 resulted in marked and selective stimulation of Tregs when administered as a single SC injection to healthy volunteers.Objectives:This multiple ascending dose study assessed the safety, tolerability, pharmacokinetics (PK), and immune effects of NKTR-358 in patients with SLE after repeated administration of SC doses. The time course and extent of changes in numbers and percentages of Tregs, conventional CD4+ and CD8+ T cells, NK cells, and cytokine levels in peripheral blood were investigated.Methods:In this double-blind, multiple ascending dose study, patients with mild to moderate SLE received 3 SC doses q2w in 4 cohorts ranging from 3.0 to 24.0 µg/kg (9 active:3 placebo per cohort); patients were followed for a total of 79 days.Results:There were no dose-limiting toxicities, deaths, or clinically significant abnormalities in either vital signs or electrocardiograms. Adverse events attributed to NKTR-358 were primarily limited to mild (grade 1) injection site reactions. At the highest dose, one subject had transient and mild (grade 1) symptoms of a flu-like syndrome after administration, without associated elevated cytokine levels, and another subject had dosing stopped due to elevated eosinophil levels. No other individual at any dose level had systemic signs or symptoms known to be associated with IL-2 therapy. No anti-drug antibodies were detected. NKTR-358 demonstrated dose-proportional PK with repeated dosing; plasma levels peaked 3-6 days post-dose and declined with a terminal half-life of ~10-13 days.The primary and consistent effect of NKTR-358 was seen on Tregs. In the four dose cohorts, dose-dependent and sustained increases in absolute numbers and percentages of circulating CD4+FoxP3+CD25brightTregs were observed. Treg levels remained elevated throughout the dosing period, peaking at Day 10 after the first administration of NKTR-358 and returning to baseline ~ 20-30 days following last administration. At 24.0 µg/kg, the mean peak increase in numbers of CD25brightTregs was 11-fold above baseline. In addition, there was an increase in Treg activation markers at doses ≥12.0 µg/kg. In contrast to effects on Tregs, no changes in percentages or numbers of conventional CD4+ or CD8+ T cells were observed at any dose tested. At the highest dose, there were low-level increases in the percentages and numbers of NK cells. Overall, NKTR-358 selectively induced Tregs, evidenced by a 12-fold increase in the mean peak Treg:CD8 ratio over baseline in the 24.0 µg/kg group.Conclusion:NKTR-358, an IL-2 conjugate Treg stimulator, was well tolerated when repeatedly administered (q2w) at doses up to 24 µg/kg. Its administration led to marked, selective, prolonged, and dose-dependent increases in circulating CD25brightTregs. This clinical study in SLE patients extends the previous results in healthy volunteers and provides strong support for continued testing of NKTR-358 as a new therapeutic in SLE and other inflammatory diseases.Disclosure of Interests:Suresh Siddhanti Shareholder of: Nektar Therapeutics, Employee of: Nektar Therapeutics, Christie Fanton Shareholder of: Nektar Therapeutics, Employee of: Nektar Therapeutics, Neha Dixit Shareholder of: Nektar Therapeutics, Employee of: Nektar Therapeutics, Lin Lu Shareholder of: Nektar Therapeutics, Employee of: Nektar Therapeutics, Vishala Chindalore Grant/research support from: Nektar Therapeutics for conducted studies, Speakers bureau: > 5 years ago, Robert Levin Grant/research support from: Payments for clinical research for industry-sponsored trials, Consultant of: Gilead, Exagen, Myriad Rheumatology, Speakers bureau: Sanofi/Genzyme, Regeneron, Bristol-Myers Squibb, AbbVie, Isam Diab: None declared, Richard Furie Grant/research support from: Nektar Therapeutics to Northwell Rheumatology to conduct this study, Consultant of: Nektar Therapeutics, Jonathan Zalevsky Shareholder of: Nektar Therapeutics, Employee of: Nektar Therapeutics, Brian Kotzin Shareholder of: Nektar Therapeutics, Employee of: Nektar Therapeutics

Plasma Thrombospondin as an Indicator of Intravascular Platelet Activation in Patients with Vasculitis

1987 ◽  
Vol 58 (03) ◽  
pp. 850-852 ◽  
Author(s):  
M B McCrohan ◽  
S W Huang ◽  
J W Sleasman ◽  
P A Klein ◽  
K J Kao
Keyword(s):  
Platelet Activation ◽  
Plasma Levels ◽  
Half Life ◽  
Degradation Products ◽  
Plasma Concentrations ◽  
Primary Source ◽  
Positive Correlation ◽  
Activation Marker ◽  
Fibrin Degradation Products ◽  
The Mean

SummaryThe use of plasma thrombospondin (TSP) concentration was investigated as an indicator of intravascular platelet activation. Patients (n = 20) with diseases that have known vasculitis were included in the study. The range and the mean of plasma TSP concentrations of patients with vasculitis were 117 ng/ml to 6500 ng/ml and 791±1412 ng/ml (mean ± SD); the range and the mean of plasma TSP concentrations of control individuals (n = 33) were 13 ng/ml to 137 ng/ml and 59±29 ng/ml. When plasma TSP concentrations were correlated with plasma concentrations of another platelet activation marker, β-thromboglobulin (P-TG), it was found that the TSP concentration inei eased exponentially as the plasma β-TG level rose. A positive correlation between plasma levels of plasma TSP and serum fibrin degradation products was also observed. The results suggest that platelets are the primary source of plasma TSP in patients with various vasculitis and that plasma TSP can be a better indicator than β-TG to assess intravascular platelet activation due to its longer circulation half life.

Effects of NO-Donors on Thrombus Formation and Microcirculation in Cerebral Vessels of the Rat

1996 ◽  
Vol 76 (01) ◽  
pp. 111-117 ◽  
Author(s):  
Yasuto Sasaki ◽  
Junji Seki ◽  
John C Giddings ◽  
Junichiro Yamamoto
Keyword(s):  
Blood Flow ◽  
Thrombus Formation ◽  
Dependent Manner ◽  
Red Cell ◽  
Cell Velocity ◽  
Red Cell Velocity ◽  
The Mean ◽  
Wall Shear ◽  
Dose Dependent

SummarySodium nitroprusside (SNP) and 3-morpholinosydnonimine (SIN-1), are known to liberate nitric oxide (NO). In this study the effects of SNP and SIN-1 on thrombus formation in rat cerebral arterioles and venules in vivo were assessed using a helium-neon (He-Ne) laser. SNP infused at doses from 10 Μg/kg/h significantly inhibited thrombus formation in a dose dependent manner. This inhibition of thrombus formation was suppressed by methylene blue. SIN-1 at a dose of 100 Μg/kg/h also demonstrated a significant antithrombotic effect. Moreover, treatment with SNP increased vessel diameter in a dose dependent manner and enhanced the mean red cell velocity measured with a fiber-optic laser-Doppler anemometer microscope (FLDAM). Blood flow, calculated from the mean red cell velocity and vessel diameters was increased significantly during infusion. In contrast, mean wall shear rates in the arterioles and venules were not changed by SNP infusion. The results indicated that SNP and SIN-1 possessed potent antithrombotic activities, whilst SNP increased cerebral blood flow without changing wall shear rate. The findings suggest that the NO released by SNP and SIN-1 may be beneficial for the treatment and protection of cerebral infarction

DISAPPEARANCE RATE OF BOVINE PROLACTIN FROM PLASMA OF FEMALE RATS STUDIED AT INTERVALS OF UP TO 160 MINUTES BY RADIOIMMUNOASSAY

1970 ◽  
Vol 64 (4) ◽  
pp. 718-725 ◽  
Author(s):  
A. A. van der Gugten ◽  
H. G. Kwa
Keyword(s):  
Intravenous Administration ◽  
Female Rats ◽  
Disappearance Rate ◽  
Blood Samples ◽  
Dose Dependent

ABSTRACT Plasma values resulting from the intravenous administration of 300, 100, 30 and 10 μ of bovine prolactin to rats on day 1 of pregnancy were followed by taking blood samples after 10, 20, 40, 80 and 160 minutes respectively. The rate of disappearance was found to be dose-dependent and to vary in time in the same rat. It is suggested that at least two processes of elimination take place: 1. a (possibly excretory) process, which can bring »unphysiologically high« prolactin levels down to approximately its treshold level of 1.7 μg/ml and 2. a process, which breaks down the hormone into »immunoreactive« polypeptides. This process can degrade 10 μg of bovine prolactin quantitatively within 10 minutes, but appears to become rapidly »saturated« by larger amounts of the hormone.

Amelioration of Carbon Tetrachloride-Induced Liver Injury by Citrus Leaf Extract

2019 ◽  
Vol 17 (4) ◽  
pp. 426-431
Author(s):  
Jin Xuezhu ◽  
Li Jitong ◽  
Nie Leigang ◽  
Xue Junlai
Keyword(s):  
Carbon Tetrachloride ◽  
Leaf Extract ◽  
Hepatic Injury ◽  
The Body ◽  
Dependent Manner ◽  
Weight Changes ◽  
Citrus Leaf ◽  
Dose Dependent ◽  
And Oxidative Stress

The main purpose of this study is to investigate the role of citrus leaf extract in carbon tetrachloride-induced hepatic injury and its potential molecular mechanism. Carbon tetrachloride was used to construct hepatic injury animal model. To this end, rats were randomly divided into 4 groups: control, carbon tetrachloride-treated, and two carbon tetrachloride + citrus leaf extract-treated groups. The results show that citrus leaf extract treatment significantly reversed the effects of carbon tetrachloride on the body weight changes and liver index. Besides, treatment with citrus leaf extract also reduced the levels of serum liver enzymes and oxidative stress in a dose-dependent manner. H&E staining and western blotting suggested that citrus leaf extract could repair liver histological damage by regulating AMPK and Nrf-2.

Synthesis of a silymarin-gold nanoparticle conjugate and analysis of its liver-protecting activity

2021 ◽  
Vol 22 ◽  
Author(s):  
Sergey Staroverov ◽  
Sergey Kozlov ◽  
Alexander Fomin ◽  
Konstantib Gabalov ◽  
Alexey Volkov ◽  
...  
Keyword(s):  
Gold Nanoparticles ◽  
Liver Disease ◽  
Carbon Tetrachloride ◽  
Glutathione Depletion ◽  
Laboratory Animals ◽  
Experimental Hepatitis ◽  
Acute Liver Disease ◽  
The Mean ◽  
Extent Of Damage ◽  
First Time

Background: The liver disease problem prompts investigators to search for new methods of liver treatment. Introduction: Silymarin (Sil) protects the liver by reducing the concentration of free radicals and the extent of damage to the cell membranes. A particularly interesting method to increase the bioavailability of Sil is to use synthesized gold nanoparticles (AuNPs) as reagents. The study considered whether it was possible to use the silymarin-AuNP conjugate as a potential liver-protecting drug. Method: AuNPs were conjugated to Sil and examine the liver-protecting activity of the conjugate. Experimental hepatitis and hepatocyte cytolysis after carbon tetrachloride actionwere used as a model system, and the experiments were conducted on laboratory animals. Result: For the first time, silymarin was conjugated to colloidal gold nanoparticles (AuNPs). Electron microscopy showed that the resultant preparations were monodisperse and that the mean conjugate diameter was 18–30 nm ± 0.5 nm (mean diameter of the native nanoparticles, 15 ± 0.5 nm). In experimental hepatitis in mice, conjugate administration interfered with glutathione depletion in hepatocytes in response to carbon tetrachloride was conducive to an increase in energy metabolism, and stimulated the monocyte–macrophage function of the liver. The results were confirmed by the high respiratory activity of the hepatocytes in cell culture. Conclusion: We conclude that the silymarin-AuNP conjugate holds promise as a liver-protecting agent in acute liver disease caused by carbon tetrachloride poisoning.

scholarly journals Mechanisms underlying the antifibrotic properties of noninhibitory PAI-1 (PAI-1R) in experimental nephritis

2009 ◽  
Vol 297 (4) ◽  
pp. F1045-F1054 ◽  
Author(s):  
Yufeng Huang ◽  
Wayne A. Border ◽  
Daniel A. Lawrence ◽  
Nancy A. Noble
Keyword(s):  
Half Life ◽  
Stable Form ◽  
Therapeutic Effects ◽  
Dependent Manner ◽  
Therapeutic Action ◽  
Protease Inhibition ◽  
Ecm Degradation ◽  
Dose Dependent ◽  
Pai 1

Administration of a mutant, noninhibitory PAI-1 (PAI-1R), reduces disease in experimental glomerulonephritis. Here we investigated the importance of vitronectin (Vn) binding, PAI-1 stability and protease binding in this therapeutic effect using a panel of PAI-1 mutants differing in half-life, protease binding, and Vn binding. PAI-1R binds Vn normally but does not inhibit proteases. PAI-1AK has a complete defect in Vn binding but retains full inhibitory activity, with a short half-life similar to wild-type (wt)-PAI-1. Mutant 14-lb is identical to wt-PAI-1 but with a longer half-life. PAI-1K has defective Vn binding, inhibits proteases normally, and has a long half-life. In vitro wt-PAI-1 dramatically inhibited degradation of mesangial cell ECM while the AK mutant had much less effect. Mutants 14-1b and PAI-1K, like wt-PAI-1, inhibited matrix degradation but PAI-1R failed to reverse this inhibition although PAI-1R reversed the wt-PAI-1-induced inhibition of ECM degradation in a plasmin-, time-, and dose-dependent manner. Thus the ability of PAI-1 to inhibit ECM degradation is dependent both on its antiproteinase activity and on maintaining an active conformation achieved either by Vn binding or mutation to a stable form. Administration of these PAI-1 mutants to nephritic rats confirmed the in vitro data; only PAI-1R showed therapeutic effects. PAI-1K did not bind to nephritic kidney, indicating that Vn binding is essential to the therapeutic action of PAI-1R. The ability of PAI-1R to remain bound to Vn even in a high-protease environment is very likely the key to its therapeutic efficacy. Furthermore, because both PAI-1R and 14-1b bound to the nephritic kidney in the same pattern and differ only in their ability to bind proteases, lack of protease inhibition is also keyed to PAI-1R's therapeutic action.

scholarly journals Dose dependent changes in propranolol half life when used as an adjunct to neuroleptic treatment

1982 ◽  
Vol 78 (1) ◽  
pp. 96-96
Author(s):  
D. H. Staniforth ◽  
N. J. Yorkston ◽  
S. A. Zaki
Keyword(s):  
Half Life ◽  
Neuroleptic Treatment ◽  
Dose Dependent

Prolactin stimulates food intake in a dose-dependent manner

1989 ◽  
Vol 256 (1) ◽  
pp. R276-R280 ◽  
Author(s):  
T. Gerardo-Gettens ◽  
B. J. Moore ◽  
J. S. Stern ◽  
B. A. Horwitz
Keyword(s):  
Food Intake ◽  
Female Rats ◽  
High Dose ◽  
Dependent Manner ◽  
Additional Control ◽  
The Mean ◽  
Ovine Prolactin ◽  
Dose Dependent ◽  
Medium Dose ◽  
Cumulative Food Intake

Lactation in the rat is marked by pronounced hyperphagia and suppression of brown fat (BAT) thermogenic capacity. We previously examined the possibility that elevated prolactin levels mediate these changes. The present study evaluated the effect of varying prolactin levels on food intake, BAT mitochondrial GDP binding, and carcass adiposity. Female rats were injected daily for 10 days with ovine prolactin at one of three doses: high = 3.0, medium = 1.0, or low = 0.3 micrograms/g body wt. Controls were injected with 0.9% NaCl. A group of uninjected rats served as an additional control. Cumulative food intake was significantly elevated in a dose-dependent manner in the prolactin-treated animals relative to the saline-injected and uninjected controls. Compared with the saline controls, the mean cumulative food intake was greatest at the high dose (20% increase), intermediate at the medium dose (17%), and smallest at the low dose (12%). Prolactin-treated rats gained significantly more weight during the experiment than did controls. Despite the hyperphagia in the prolactin-treated rats, no significant differences in BAT mitochondrial GDP binding were observed among the five groups. These data indicate that elevated prolactin levels stimulate food intake in a dose-dependent manner and that this hyperphagia is not accompanied by an increase in BAT mitochondrial GDP binding.

Sign in / Sign up

Export Citation Format

Share Document