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

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

1982 ◽  
Vol 76 (1) ◽  
pp. 62-65 ◽  
Author(s):  
D. H. Staniforth ◽  
N. J. Yorkston ◽  
Saniha A. Zaki
Keyword(s):  
Half Life ◽  
Neuroleptic Treatment ◽  
Dose Dependent

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.

Follicle-stimulating hormone stimulates inhibin in the serum of male monkeys (Macaca mulatta)

1990 ◽  
Vol 122 (1) ◽  
pp. 96-100 ◽  
Author(s):  
Ulrich Fingscheidt ◽  
Gerhard F. Weinbauer ◽  
Shafiq A. Khan ◽  
Eberhard Nieschlag
Keyword(s):  
Macaca Mulatta ◽  
Half Life ◽  
Rhesus Monkeys ◽  
Follicle Stimulating Hormone ◽  
Serum Levels ◽  
Lag Time ◽  
Dependent Manner ◽  
Control Serum ◽  
Dose Dependent ◽  
Stimulating Hormone

Abstract. Three adult rhesus monkeys were injected intramuscularly with human FSH at doses of 2, 10 or 25 IU/kg in a cross-over design with 3-week intervals between injections. On each occasion a fourth animal received saline only as control. Serum levels of exogenous FSH were monitored by a fluoroimmunoassay specific for human FSH. Serum inhibin was measured by a heterologous radioimmunoassay. Each FSH injection was followed by a rise in serum inhibin in a dose-dependent manner. The half-life of human FSH in rhesus monkeys ranged from 25.1 to 32.9 h with no significant differences between doses. The rise of inhibin occurred with a lag time of 53.3 to 61.9 h after injection of FSH, independent of the dose administered. These findings support the concept that inhibin secretion in male primates is stimulated by FSH.

In Vivo Assay for Neuroleptic Receptor Binding in the Striatum

1987 ◽  
Vol 151 (6) ◽  
pp. 824-830 ◽  
Author(s):  
H. Cambon ◽  
J. C. Baron ◽  
J. P. Boulenger ◽  
C. Loc'h ◽  
E. Zarifian ◽  
...  
Keyword(s):  
Corpus Striatum ◽  
Specific Binding ◽  
Receptor Occupancy ◽  
Saturation Curve ◽  
Validity And Reliability ◽  
Neuroleptic Treatment ◽  
Clear Cut ◽  
Therapeutic Doses ◽  
Dose Dependent

Using PET, we investigated the potency in six patients of therapeutic doses of neuroleptic drugs for preventing specific binding of trace doses of intravenously administered 76Br labelled bromospiperone to corpus striatum in vivo. Measured receptor occupancy showed a clear-cut dose-dependent saturation curve with increasing daily oral dose of neuroleptics, indicating the validity and reliability of the method when used as an in vivo radioreceptor assay. Following drug withdrawal in eight patients, recovery to normal or supranormal receptor availability occurred in a matter of days. The results demonstrate an approach that may help resolve controversies about, and design better strategies for, neuroleptic treatment schedules.

Pharmacokinetics and Tolerability of a New Low Molecular Mass Heparin (RO-11) in Healthy Volunteers – A Dose-Finding Study within the Therapeutical Range

1997 ◽  
Vol 77 (01) ◽  
pp. 133-136 ◽  
Author(s):  
Liliana Falkon ◽  
Miriam M Bayés ◽  
Guillem Frontera ◽  
Mercè Garí ◽  
Manel Barbanoj ◽  
...  
Keyword(s):  
Phase I ◽  
Molecular Mass ◽  
Half Life ◽  
Dose Finding ◽  
Dose Effect ◽  
Efficacy And Safety ◽  
First Order ◽  
Finding Study ◽  
Dose Finding Study ◽  
Dose Dependent

SummaryThis paper reports on the results of a Phase I, dose-finding study with a new low molecular mass heparin (LMMH) called RO-11. The study focused on pharmacokinetics, dose-effect relationship and on tolerability of three single subcutaneous (SC) doses within the therapeutical range. After the injection of 7,500, 9,000 and 12,500 anti-FXa IU, the anti-FXa effect peaked between 3-6 h and showed a dose-dependent response. The absorption and elimination were first-order processes and the long half-life (>5 h) kept constant after increasing doses. The compound was tolerated very well and no clinically relevant prolongation of APTT, prothrombin and thrombin clotting tests was observed. At the dose of 7,500 IU, which corresponded to 110 anti-FXa IU/Kg, RO-11 exerted anti-FXa effect for at least 18-20 h. We recommend using this dose in a single SC injection, to evaluate the efficacy and safety of RO-11 in the initial treatment of DVT or PE.

scholarly journals In Vivo Pharmacodynamic Activity of the Glycopeptide Dalbavancin

2007 ◽  
Vol 51 (5) ◽  
pp. 1633-1642 ◽  
Author(s):  
David Andes ◽  
William A. Craig
Keyword(s):  
Half Life ◽  
Dose Range ◽  
Lung Infection ◽  
Free Drug ◽  
Infection Model ◽  
Gram Positive ◽  
Elimination Half Life ◽  
Elimination Half ◽  
Dose Dependent

ABSTRACT Dalbavancin is a lipoglycopeptide antibiotic with broad-spectrum activity against gram-positive cocci and a markedly prolonged serum elimination half-life. We used the neutropenic murine thigh and lung infection models to characterize the pharmacodynamics of dalbavancin. Single-dose pharmacokinetic studies demonstrated linear kinetics and a prolonged elimination half-life which ranged from 7.6 to 13.1 h over the dose range of 2.5 to 80 mg/kg of body weight. The level of protein binding in mouse serum was 98.4%. The time course of in vivo activity of dalbavancin over the same dose range was examined in neutropenic ICR Swiss mice infected with a strain of either Streptococcus pneumoniae or Staphylococcus aureus by using the thigh infection model. The burden of organisms for S. pneumoniae was markedly reduced over the initial 24 h of study, and organism regrowth was suppressed in a dose-dependent fashion for up to the entire 96 h of study following dalbavancin doses of 2.5 mg/kg or greater. Dalbavancin doses of 20 mg/kg or greater resulted in less killing of S. aureus but were still followed by a prolonged suppression of regrowth. Multiple-dosing-regimen studies with the same organisms were used to determined which of the pharmacodynamic indices (maximum concentration in serum [C max]/MIC, area under the concentration-versus-time curve [AUC]/MIC, or the duration of time that levels in serum exceed the MIC) best correlated with treatment efficacy. These studies used a dose range of 3.8 to 480 mg/kg/6 days fractionated into 2, 4, 6, or 12 doses over the 144-h dosing period. Nonlinear regression analysis was used to examine the data fit with each pharmacodynamic index. Dalbavancin administration by the use of large, widely spaced doses was the most efficacious for both organisms. Both the 24-h AUC/MIC and the C max/MIC parameters correlated well with the in vivo efficacy of treatment against S. pneumoniae and S. aureus (for 24-h AUC/MIC, R 2 = 78 and 77%, respectively; for C max/MIC, R 2 = 90 and 57%, respectively). The free-drug 24-h AUC/MICs required for a bacteriostatic effect were 17 ± 7 for five S. pneumoniae isolates. A similar treatment endpoint for the treatment against five strains of S. aureus required a larger dalbavancin exposure, with a mean free-drug 24-h AUC/MIC of 265 ± 143. Beta-lactam resistance did not affect the pharmacodynamic target. The dose-response curves were relatively steep for both species; thus, the pharmacodynamic target needed to achieve organism reductions of 1 or 2 log10 in the mice were not appreciably larger (1.3- to 1.6-fold). Treatment was similarly efficacious in neutropenic mice and in the lung infection model. The dose-dependent efficacy and prolonged elimination half-life of dalbavancin support the widely spaced regimens used in clinical trials. The free-drug 24-h AUC/MIC targets identified in these studies should be helpful for discerning rational susceptibility breakpoints. The current MIC90 for the target gram-positive organisms would fall within this value.

scholarly journals Compartmental Pharmacokinetics and Tissue Drug Distribution of the Pradimicin Derivative BMS 181184 in Rabbits

1998 ◽  
Vol 42 (10) ◽  
pp. 2700-2705 ◽  
Author(s):  
Andreas H. Groll ◽  
Tin Sein ◽  
Vidas Petraitis ◽  
Ruta Petraitiene ◽  
Diana Callender ◽  
...  
Keyword(s):  
Single Dose ◽  
Half Life ◽  
Peak Plasma ◽  
Volume Of Distribution ◽  
Multiple Dosing ◽  
Time Curve ◽  
Dose Administration ◽  
Single Dose Administration ◽  
Elimination Half ◽  
Dose Dependent

ABSTRACT The pharmacokinetics of the antifungal pradimicin derivative BMS 181184 in plasma of normal, catheterized rabbits were characterized after single and multiple daily intravenous administrations of dosages of 10, 25, 50, or 150 mg/kg of body weight, and drug levels in tissues were assessed after multiple dosing. Concentrations of BMS 181184 were determined by a validated high-performance liquid chromatography method, and plasma data were modeled into a two-compartment open model. Across the investigated dosage range, BMS 181184 demonstrated nonlinear, dose-dependent kinetics with enhanced clearance, reciprocal shortening of elimination half-life, and an apparently expanding volume of distribution with increasing dosage. After single-dose administration, the mean peak plasma BMS 181184 concentration (C max) ranged from 120 μg/ml at 10 mg/kg to 648 μg/ml at 150 mg/kg; the area under the concentration-time curve from 0 to 24 h (AUC0–24) ranged from 726 to 2,130 μg · h/ml, the volume of distribution ranged from 0.397 to 0.799 liter/kg, and the terminal half-life ranged from 4.99 to 2.31 h, respectively (P < 0.005 toP < 0.001). No drug accumulation in plasma occurred after multiple daily dosing at 10, 25, or 50 mg/kg over 15 days, although mean elimination half-lives were slightly longer. Multiple daily dosing at 150 mg/kg was associated with enhanced total clearance and a significant decrease in AUC0–24 below the values obtained at 50 mg/kg (P < 0.01) and after single-dose administration of the same dosage (P < 0.05). Assessment of tissue BMS 181184 concentrations after multiple dosing over 16 days revealed substantial uptake in the lungs, liver, and spleen and, most notably, dose-dependent accumulation of the drug within the kidneys. These findings are indicative of dose- and time-dependent elimination of BMS 181184 from plasma and renal accumulation of the compound after multiple dosing.

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.

scholarly journals Circulating Half-Life of PEGylated Recombinant Methioninase Holoenzyme Is Highly Dose Dependent on Cofactor Pyridoxal-5′-Phosphate

2004 ◽  
Vol 64 (16) ◽  
pp. 5775-5778 ◽  
Author(s):  
Zhijian Yang ◽  
Xinghua Sun ◽  
Shukuan Li ◽  
Yuying Tan ◽  
Xiaoen Wang ◽  
...  
Keyword(s):  
Half Life ◽  
Dose Dependent
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