scholarly journals Pharmacodynamics and pharmacokinetics of dermatan sulfate in humans

Blood ◽  
1989 ◽  
Vol 74 (5) ◽  
pp. 1577-1582
Author(s):  
F Dol ◽  
G Houin ◽  
M Rostin ◽  
JL Montastruc ◽  
D Dupouy ◽  
...  
Keyword(s):  
Dermatan Sulfate ◽  
Plasma Concentrations ◽  
Volume Of Distribution ◽  
Pharmacokinetic Parameters ◽  
Intravenous Injections ◽  
Routes Of Administration ◽  
Chromogenic Assay ◽  
Interindividual Variations ◽  
Pharmacokinetic Properties ◽  
Hemorrhagic Risk

Dermatan sulfate (DS), a catalyst of the thrombin-heparin cofactor II interaction, has antithrombotic activity and is devoid of significant hemorrhagic risk in several animal models. We investigated the pharmacodynamic and pharmacokinetic properties of DS in humans. DS was injected in single bolus intravenous injections of four increasing doses (0.5, 1, 1.5, 2 mg/kg) to six healthy volunteers. The resulting anticoagulant activities were assessed by the activated partial thromboplastin time (APTT) and the thrombin clotting time (TCT). There were dose-dependent prolongations of the APTT and TCT, and the anticoagulant activities disappeared in less than three hours. The pharmacokinetic parameters were calculated from the plasma concentrations of DS measured with a new chromogenic assay. The volume of distribution was approximately 1.8 times greater than the theoretical plasma volume and was independent of dose. In contrast, the clearance decreased with dose and the terminal half-life ranged from 0.45 +/- 0.08 hours at 0.5 mg/kg to 0.72 +/- 0.11 hours (mean +/- SD) at 2 mg/kg. The bioavailabilities of subcutaneous (SC) and intramuscular (IM) administration relative to those of intravenous administration were determined in 12 other volunteers. The respective bioavailabilities were 24.7% +/- 12.9% and 12.4% +/- 9.2% for SC and IM administration. There was no detectable change in the APTT and the TCT when the volunteers were injected with 1.5 mg/kg SC or IM. In addition, the pharmacokinetic parameters derived from plasma concentrations of DS showed considerable interindividual variations by the two later routes of administration. Peak concentrations were noted 2.7 +/- 1.3 hours after SC injection and 4.3 +/- 4.9 hours after IM injection. The average peak concentrations were 0.7 +/- 0.3 and 0.4 +/- 0.2 mg/L after SC and IM injections, respectively. The half-lives of DS were 7.9 +/- 6.5 hours (SC) and 6.3 +/- 7.4 hours (IM). No adverse reaction to DS was recorded during this study.

scholarly journals Pharmacodynamics and pharmacokinetics of dermatan sulfate in humans

Blood ◽  
1989 ◽  
Vol 74 (5) ◽  
pp. 1577-1582 ◽  
Author(s):  
F Dol ◽  
G Houin ◽  
M Rostin ◽  
JL Montastruc ◽  
D Dupouy ◽  
...  
Keyword(s):  
Dermatan Sulfate ◽  
Plasma Concentrations ◽  
Volume Of Distribution ◽  
Pharmacokinetic Parameters ◽  
Intravenous Injections ◽  
Routes Of Administration ◽  
Chromogenic Assay ◽  
Interindividual Variations ◽  
Pharmacokinetic Properties ◽  
Hemorrhagic Risk

Abstract Dermatan sulfate (DS), a catalyst of the thrombin-heparin cofactor II interaction, has antithrombotic activity and is devoid of significant hemorrhagic risk in several animal models. We investigated the pharmacodynamic and pharmacokinetic properties of DS in humans. DS was injected in single bolus intravenous injections of four increasing doses (0.5, 1, 1.5, 2 mg/kg) to six healthy volunteers. The resulting anticoagulant activities were assessed by the activated partial thromboplastin time (APTT) and the thrombin clotting time (TCT). There were dose-dependent prolongations of the APTT and TCT, and the anticoagulant activities disappeared in less than three hours. The pharmacokinetic parameters were calculated from the plasma concentrations of DS measured with a new chromogenic assay. The volume of distribution was approximately 1.8 times greater than the theoretical plasma volume and was independent of dose. In contrast, the clearance decreased with dose and the terminal half-life ranged from 0.45 +/- 0.08 hours at 0.5 mg/kg to 0.72 +/- 0.11 hours (mean +/- SD) at 2 mg/kg. The bioavailabilities of subcutaneous (SC) and intramuscular (IM) administration relative to those of intravenous administration were determined in 12 other volunteers. The respective bioavailabilities were 24.7% +/- 12.9% and 12.4% +/- 9.2% for SC and IM administration. There was no detectable change in the APTT and the TCT when the volunteers were injected with 1.5 mg/kg SC or IM. In addition, the pharmacokinetic parameters derived from plasma concentrations of DS showed considerable interindividual variations by the two later routes of administration. Peak concentrations were noted 2.7 +/- 1.3 hours after SC injection and 4.3 +/- 4.9 hours after IM injection. The average peak concentrations were 0.7 +/- 0.3 and 0.4 +/- 0.2 mg/L after SC and IM injections, respectively. The half-lives of DS were 7.9 +/- 6.5 hours (SC) and 6.3 +/- 7.4 hours (IM). No adverse reaction to DS was recorded during this study.

scholarly journals Population Pharmacokinetics of Lumefantrine in Pregnant Women Treated with Artemether-Lumefantrine for Uncomplicated Plasmodium falciparum Malaria

2009 ◽  
Vol 53 (9) ◽  
pp. 3837-3846 ◽  
Author(s):  
Joel Tarning ◽  
Rose McGready ◽  
Niklas Lindegardh ◽  
Elizabeth A. Ashley ◽  
Mupawjay Pimanpanarak ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Pregnant Women ◽  
Population Pharmacokinetics ◽  
Plasma Concentrations ◽  
Plasmodium Falciparum Malaria ◽  
Volume Of Distribution ◽  
Pharmacokinetic Parameters ◽  
Population Pharmacokinetic ◽  
Increased Risk ◽  
Pharmacokinetic Properties

ABSTRACT Artemether-lumefantrine has become one of the most widely used antimalarial drugs in the world. The objective of this study was to determine the population pharmacokinetic properties of lumefantrine in pregnant women with uncomplicated multidrug-resistant Plasmodium falciparum malaria on the northwestern border of Thailand. Burmese and Karen women (n = 103) with P. falciparum malaria and in the second and third trimesters of pregnancy were treated with artemether-lumefantrine (80/480 mg) twice daily for 3 days. All patients provided five capillary plasma samples for drug quantification, and the collection times were randomly distributed over 14 days. The concentration-time profiles of lumefantrine were assessed by nonlinear mixed-effects modeling. The treatment failure rate (PCR-confirmed recrudescent infections at delivery) was high; 16.5% (95% confidence interval, 9.9 to 25.1). The population pharmacokinetics of lumefantrine were described well by a two-compartment open model with first-order absorption and elimination. The final model included interindividual variability in all pharmacokinetic parameters and a linear covariate relationship between the estimated gestational age and the central volume of distribution. A high proportion of all women (40%, 41/103) had day 7 capillary plasma concentrations of <355 ng/ml (which corresponds to approximately <280 ng/ml in venous plasma), a threshold previously associated with an increased risk of therapeutic failure in nonpregnant patients in this area. Predictive modeling suggests that a twice-daily regimen given for 5 days would be preferable in later pregnancy. In conclusion, altered pharmacokinetic properties of lumefantrine contribute to the high rates of failure of artemether-lumefantrine treatment in later pregnancy. Dose optimization is urgently needed.

Human Pharmacokinetics and Pharmacodynamics of MF 701 Dermatan Sulfate Administered by Continuous Intravenous Infusion

1990 ◽  
Vol 64 (02) ◽  
pp. 256-259 ◽  
Author(s):  
Giancarlo Agnelli ◽  
Benilde Cosmi ◽  
Cinzia Renga ◽  
Fiorella Federici ◽  
Giuseppe G Necil ◽  
...  
Keyword(s):  
Pharmacokinetic Model ◽  
Dermatan Sulfate ◽  
Plasma Concentrations ◽  
Volume Of Distribution ◽  
Human Pharmacokinetics ◽  
Bolus Administration ◽  
Thrombin Inhibition ◽  
Chromogenic Assay ◽  
Single Compartment ◽  
Human Thrombin

SummaryThe pharmacokinetics and haemostatic effects of MF 701 dermatan sulfate (DS) administered by i. v. infusion were studied in 11 healthy volunteers. Each subject received 0.6 mg kg-1 h-1 MF 701 for 10 h. DS plasma concentrations were measured by a chromogenic assay based on the catalysis of thrombin inhibition by HCII. DS plasma levels followed a single compartment pharmacokinetic model, with a half-life of 1.28 ± 0.46 h, a plasma clearance of 2.75 ± 0.46 1/h and a volume of distribution of 4.92 ± 1.36 1 (means ± SD). Steady-state was reached 3 to 6 h after infusion started. The maximal DS plasma concentration was 16.4 ± 5.7 μg/ml. Maximal APTT prolongation over pre-infusion values was 42 ± 7%; TCT performed with bovine and human thrombin was prolonged by 16 ± 7% and 83 ± 35% respectively. No anti-IIa or anti-Xa activities were detected by chromogenic tests. The treatment was well tolerated. The pharmacokinetics of MF 701 infusion are consistent with those previously described after i. v. bolus administration. The infusion of MF 701 allows fast achievement and steady maintenance of elevated DS plasma concentrations.

Pharmacokinetic Evaluation of anti-HIV Drug Interactions: Effect of Zidovudine on 2′-3′-Dideoxyinosine Kinetics in Monkeys

1993 ◽  
Vol 4 (3) ◽  
pp. 155-159 ◽  
Author(s):  
M. Qian ◽  
A. R. Swagler ◽  
M. Mehta ◽  
C.T. Vishwanathan ◽  
J. M. Gallo
Keyword(s):  
Dose Group ◽  
Plasma Concentrations ◽  
Volume Of Distribution ◽  
Pharmacokinetic Parameters ◽  
High Dose ◽  
Combination Regimen ◽  
Time Profiles ◽  
Elimination Half ◽  
Constant Rate ◽  
Rate Infusion

The current investigation was conducted to determine if zidovudine (AZT) altered the pharmacokinetics of dideoxyinosine (ddl) in non-hurnan primates, an appropriate animal model for AZT and ddl pharmacokinetics in human. Each of nine animals received 20 mg kg−1 of ddl intravenously in the absence and presence of two different dosage regimens of AZT. For each combination regimen, AZT was administered as a combined i.v. bolus-constant rate infusion regimen for 30 min that produced AZT plasma concentrations of about 4 μg ml−1 in six animals (low dose group) and 11 μg ml−1 in three others (high dose group). Serial blood samples were collected, and pharmacokinetic parameters for ddl were calculated based on plasma ddl concentrations measured by HPLC techniques. The pharmacokinetics of ddl given alone in the first phase of the low ( n = 6) and high ( n = 6) dose AZT groups, resulted in a mean elimination half-life 1.54 and 1.9h, a mean total clearance of 0.62 and 0.731 h−1 kg−1, and a mean steady state volume of distribution of 1.02 and 0.891 kg−1, respectively. Following combined ddl and AZT administrations, in both the low and high dose AZT groups, plasma concentration-time profiles of ddl were similar for each monkey, and no statistical differences were observed in the pharmacokinetic parameters compared to those obtained when ddl was given alone. The fact that AZT does not alter the pharmacokinetics of ddl at the range of AZT dose studied provides a basis for rational dosage design for combined ddl and AZT treatments in HIV infection.

Pharmacokinetics of Dermatan Sulfate in the Rabbit After Intravenous Injection

1988 ◽  
Vol 59 (02) ◽  
pp. 255-258 ◽  
Author(s):  
F Dol ◽  
G Houin ◽  
D Dupouy ◽  
Y Cadroy ◽  
C Caranobe ◽  
...  
Keyword(s):  
Biological Activity ◽  
Low Molecular Weight Heparin ◽  
Dermatan Sulfate ◽  
Biological Activities ◽  
Pharmacokinetic Profile ◽  
Volume Of Distribution ◽  
Low Molecular Weight ◽  
Antithrombotic Agent ◽  
Heparin Cofactor Ii ◽  
Pharmacokinetic Properties

SummaryTo investigate the pharmacokinetic properties of dermatan sulfate (DS), a new potential antithrombotic agent, two different approaches were used. In the first one, DS was derivatized with 3-4 hydroxyphenyl propionic acid N hydroxysuccinimide ester (SHPP) and iodinated. The labelled derivative was injected by IV route to rabbits with increasing doses of unlabelled compound ranging from 20 to 4000 μg/kg. The disappearance of DS from plasma was characterized by measuring both the circulating radioactivity and the biological activity using an original assay based upon the catalysis of heparin cofactor II – thrombin formation. The radioactivity data indicated that the volume of distribution, the clearance and the half life of the tracer were independent of the dose of DS injected. DS concentrations measured by the bioassay indicated that more than 90% were cleared with half lives close to those calculated from the radioactivity data; the remaining biological activity was cleared at a slower rate. Experiments performed with bi-nephrectomized animals indicated that the kidneys play a major role in the elimination of DS or of its metabolites which may have a residual biological activity. In the second set of experiments, unlabelled DS was delivered under continuous intravenous infusion for 5 hours at 5 increasing doses ranging from 160 to 4200 μg/kg/h. The biological activities were used to measure the plateau concentration of DS: there was a linear relationship between the dose delivered and the plasma concentration. These data indicate that the pharmacokinetic profile of DS is very close to that of low molecular weight heparin, and quite different from that of SH.

scholarly journals Aspects of Theophylline Clearance in Children

1997 ◽  
Vol 25 (5) ◽  
pp. 497-501 ◽  
Author(s):  
B. J. Anderson ◽  
N. H. G. Holford ◽  
G. A. Woollard
Keyword(s):  
Plasma Concentrations ◽  
Volume Of Distribution ◽  
Pharmacokinetic Parameters ◽  
Parameter Estimates ◽  
Power Model ◽  
Theophylline Clearance ◽  
Concentration Data ◽  
Model Parameter ◽  
Age Related ◽  
Menten Constant

Michaelis-Menten pharmacokinetic parameters for theophylline were estimated in a three-month infant following an accidental overdose of intravenous aminophylline. Fitting of time-concentration data was performed using nonlinear regression with MKMODEL. A mixed order elimination model was superior to a first order model. Parameter estimates were standardized to a 70 kg human using an allometric power model. Parameter estimates (SE) were: maximum rate of metabolism (Vmax) 71(42) mg.h–1, Michaelis-Menten constant (Km) 32.3 (33.5) mg.l–1, volume of distribution (Vd) 46.9 (2.6) l. This Michaelis-Menten constant is lower than that reported for adults and consequently non-linear elimination will occur at lower plasma concentrations in infants than in adults. Theophylline clearance has traditionally been reported as directly proportional to body weight. This per kilogram model gives an erroneous impression that clearance is greatest in early childhood and then decreases with age until adult rates are reached in late adolescence. Age-related clearance values reported in the literature were reviewed using an allometric 3/4 power model. This size model demonstrates that clearance increases in infancy and reaches adult rates in the first one to two years of life.

THE PHARMACOKINETICS OF 125-I DERMATAN SULFATE IN THE RABBIT

1987 ◽  
Author(s):  
F Dol ◽  
G Houin ◽  
D Dupouy ◽  
C Caranobe ◽  
Y Cadroy ◽  
...  
Keyword(s):  
Biological Activity ◽  
Dermatan Sulfate ◽  
Ex Vivo ◽  
Biological Activities ◽  
Volume Of Distribution ◽  
Pharmacokinetic Parameters ◽  
Antithrombotic Agent ◽  
Heparin Cofactor Ii ◽  
Order Of Magnitude ◽  
Chloramine T

We have determined the main pharmacokinetic parameters of dermatan sulfate (DS), a catalyst of IIa-heparin cofactor II (HC II) interaction which presents antithrombotic properties in the rabbit. DS (Pharmuka, France) was conjugated with SHPP and iodinated using the chloramine T method. The labelled derivative had the same MW distribution and biological activities than.the native one. Rabbits were injected by 5 ucies of 125I-DS (0.6 ug) and increasing doses of unlabelled DS. Serial blood samples were collected to measure cpm disappearance and, in some cases, residual biological activity was determined (ex vivo quantitation of IIa- 125I-HC II complexes). The cpm curves were broken into 3 exponentials : alpha, beta and gamma. The beta exponential was closely superimposable to the curves of biological activity disappearance. The main pharmacokinetic parameters are indicated in the Table (mean ± SD) : there was a slight (non-significant) tendency to the half life (Tl/2) prolongation and to the reduction of both the clearance (cl) and the volume of distribution (Vd). Thus after IV injection, the pharmacokinetics of DS mimics that of LMW-heparin in the rabbit : Tl/2 is in the same order of magnitude and independent of the dose delivered. These results are promising for the future development of this compound as an antithrombotic agent.

scholarly journals dendPoint: a web resource for dendrimer pharmacokinetics investigation and prediction

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Lisa M. Kaminskas ◽  
Douglas E. V. Pires ◽  
David B. Ascher
Keyword(s):  
Physicochemical Properties ◽  
Volume Of Distribution ◽  
Pharmacokinetic Parameters ◽  
Success Rates ◽  
Web Resource ◽  
Development Costs ◽  
Large Numbers ◽  
Pharmacokinetic Properties ◽  
User Friendly

Abstract Nanomedicine development currently suffers from a lack of efficient tools to predict pharmacokinetic behavior without relying upon testing in large numbers of animals, impacting success rates and development costs. This work presents dendPoint, the first in silico model to predict the intravenous pharmacokinetics of dendrimers, a commonly explored drug vector, based on physicochemical properties. We have manually curated the largest relational database of dendrimer pharmacokinetic parameters and their structural/physicochemical properties. This was used to develop a machine learning-based model capable of accurately predicting pharmacokinetic parameters, including half-life, clearance, volume of distribution and dose recovered in the liver and urine. dendPoint successfully predicts dendrimer pharmacokinetic properties, achieving correlations of up to r = 0.83 and Q2 up to 0.68. dendPoint is freely available as a user-friendly web-service and database at http://biosig.unimelb.edu.au/dendpoint. This platform is ultimately expected to be used to guide dendrimer construct design and refinement prior to embarking on more time consuming and expensive in vivo testing.

Sufentanil pharmacokinetics in a full-term neonate treated with extracorporeal membrane oxygenation: a case report

Perfusion ◽  
2019 ◽  
Vol 34 (5) ◽  
pp. 433-436 ◽  
Author(s):  
Pavla Pokorná ◽  
Martin Šíma ◽  
Václav Vobruba ◽  
Martina Bašková ◽  
Lenka Posch ◽  
...  
Keyword(s):  
Drug Interaction ◽  
Case Report ◽  
Extracorporeal Membrane Oxygenation ◽  
Plasma Concentrations ◽  
Volume Of Distribution ◽  
Pharmacokinetic Parameters ◽  
Pharmacokinetic Data ◽  
Analgesic Drug ◽  
Membrane Oxygenation ◽  
Ischemic Encephalopathy

Introduction: Sufentanil is a potent analgesic drug used for pain management. A few studies describe the pharmacokinetics of sufentanil in neonates; however, no pharmacokinetic data about sufentanil during extracorporeal membrane oxygenation have been published yet. Case report: A 1-day-old neonate with moderate hypoxic–ischemic encephalopathy received veno-arterial extracorporeal membrane oxygenation support for refractory respiratory and circulatory failure. Sufentanil plasma concentrations were determined during both extracorporeal membrane oxygenation (n = 14) and non–extracorporeal membrane oxygenation (n = 17) period. Based on these measurements, individual sufentanil pharmacokinetic parameters were calculated. Discussion: We observed increased sufentanil volume of distribution (11.6 vs 5.6 L/kg) and decreased sufentanil clearance (0.535 vs 0.746 L/h/kg) in extracorporeal membrane oxygenation period. The increment of volume of distribution was attributed to ECMO influence, while difference in clearance was probably due to drug interaction. Conclusions: This is the first description of sufentanil pharmacokinetics in neonate treated with extracorporeal membrane oxygenation. We observed considerably larger volume of distribution during extracorporeal membrane oxygenation period in comparison with non–extracorporeal membrane oxygenation period.

scholarly journals Pharmacokinetics and Safety of Mitragynine in Beagle Dogs

Planta Medica ◽  
2020 ◽  
Vol 86 (17) ◽  
pp. 1278-1285 ◽  
Author(s):  
Elizabeth A. Maxwell ◽  
Tamara I. King ◽  
Shyam H. Kamble ◽  
Kanumuri Siva Rama Raju ◽  
Erin C. Berthold ◽  
...  
Keyword(s):  
Peak Plasma ◽  
Plasma Concentrations ◽  
Compartmental Analysis ◽  
Ultra Performance Liquid Chromatography ◽  
Volume Of Distribution ◽  
Pharmacokinetic Studies ◽  
Beagle Dogs ◽  
Limit Of Quantification ◽  
Significant Information ◽  
Pharmacokinetic Properties

AbstractMitragynine is the most abundant psychoactive alkaloid derived from the leaves of Mitragyna speciosa (kratom), a tropical plant indigenous to regions of Southeast Asia. Mitragynine displays a moderate affinity to opioid receptors, and kratom is often self-prescribed to treat pain and/or opioid addiction. The purpose of this study was to investigate the safety and pharmacokinetic properties of mitragynine in the dog. Single dose oral (5 mg/kg) and intravenous (0.1 mg/kg) pharmacokinetic studies of mitragynine were performed in female beagle dogs. The plasma concentrations of mitragynine were measured using ultra-performance liquid chromatography coupled with a tandem mass spectrometer, and the pharmacokinetic properties were analyzed using non-compartmental analysis. Following intravenous administration, mitragynine showed a large volume of distribution (Vd, 6.3 ± 0.6 L/kg) and high clearance (Cl, 1.8 ± 0.4 L/h/kg). Following oral mitragynine dosing, first peak plasma (Cmax, 278.0 ± 47.4 ng/mL) concentrations were observed within 0.5 h. A potent mu-opioid receptor agonist and active metabolite of mitragynine, 7-hydroxymitragynine, was also observed with a Cmax of 31.5 ± 3.3 ng/mL and a Tmax of 1.7 ± 0.6 h in orally dosed dogs while its plasma concentrations were below the lower limit of quantification (1 ng/mL) for the intravenous study. The absolute oral bioavailability of mitragynine was 69.6%. Administration of mitragynine was well tolerated, although mild sedation and anxiolytic effects were observed. These results provide the first detailed pharmacokinetic information for mitragynine in a non-rodent species (the dog) and therefore also provide significant information for allometric scaling and dose predictions when designing clinical studies.

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