Oral administration of a microencapsulated low-molecular-weight heparin to rabbits: Anti-Xa and anti-IIa profiles

2010 ◽  
Vol 103 (06) ◽  
pp. 1254-1267 ◽  
Author(s):  
Lucie Javot ◽  
Anne Sapin ◽  
Julien Scala-Bertola ◽  
Claude Vigneron ◽  
Thomas Lecompte ◽  
...  
Keyword(s):  
Oral Administration ◽  
Subcutaneous Injection ◽  
Double Emulsion ◽  
Oral Dosage ◽  
Pharmacokinetic Parameters ◽  
Low Molecular Weight ◽  
Eudragit Rs ◽  
Long Time

SummaryThe development of heparin oral form has been a subject of international research for a long time. Promising results have been obtained in vivo in terms of anti-Xa activity with different strategies and notably microparticles but studies concerning the anti-IIa activity and the anti-Xa/anti-IIa ratio have never been presented. Anti-Xa activities, anti-IIa activities and anti-Xa/anti-IIa ratios provided by nadroparin Eudragit→ RS and poly (D,L-lactic-co-glycolic acid) (PLGA) microparticles were determined in vitro and in vivo and an evaluation of their pharmacokinetic parameters compared to subcutaneous injection was performed. Nadroparin was encapsulated into microparticles prepared by the double emulsion method using Eudragit→ RS alone or in mixture with PLGA of two kinds, i.e. with (PLGA S) or without (PLGA H) esterification of the acid ending. Microparticles characterisation was performed (size, anti-Xa and anti-IIa activities entrapped and released) before their oral administration in rabbits. In vitro anti-Xa/anti-IIa ratios released from nadroparin microparticles were higher than the ratio of the commercial solution. After oral administration, whatever the formulation, sustained anti-Xa and anti-IIa activities were obtained compared to the subcutaneous injection with a peak concentration at 4 hours (up to 0.59 anti-Xa U/ml and 0.11 anti-IIa U/ml for PLGA S 50% / ERS 50% formulation). Anti-Xa and anti-IIa relative bioavailabilities were high, up to 40% (ERS 100% formulation). Anti-Xa/anti-IIa ratios were within range already obtained for subcutaneous injection, i.e. between 5 and 15. Nadroparin microparticles of nadroparin are promising oral dosage form performing sustained and well controlled anti-Xa, anti-IIa activities and anti-Xa/anti-IIa ratio.

scholarly journals Enhanced Dissolution and Oral Bioavailability of Cyclosporine A: Microspheres Based on αβ-Cyclodextrins Polymers

Pharmaceutics ◽  
2018 ◽  
Vol 10 (4) ◽  
pp. 285 ◽  
Author(s):  
Malika Lahiani-Skiba ◽  
Francois Hallouard ◽  
Frederic Bounoure ◽  
Nicolas Milon ◽  
Youness Karrout ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Secondary Structure ◽  
Oral Administration ◽  
Drug Delivery System ◽  
Delivery System ◽  
Cyclosporine A ◽  
Polymer Mixture ◽  
Pharmacokinetic Parameters

Cyclosporine (CsA) has a selective property of suppressing various T-lymphocyte functions. This is of utmost importance in preventing allograft rejection by several organ transplantations, as well as in the treatment of systemic and local autoimmune disorders. However, the poor water solubility of CsA can be a major hurdle for its absorption into the blood stream, which leads to low bioavailability and thus less efficacy. The aim of this study was to prepare, characterize, and evaluate in vitro as well as in vivo, the potential of the innovative CsA drug delivery system. The latter contains CsA in spherical amorphous solid dispersion (SASD) which is embedded in an original α-cyclodextrin and β-cyclodextrin polymer mixture (Poly-αβ-CD) as a multifunctional amorphous carrier. The new developed SASD formulation showed that CsA was molecularly dispersed in αβ-cyclodextrins in an amorphous form, as was confirmed by physicochemical characterization studies. Interestingly, the peptide secondary structure, and thus, the drug activity was not impacted by the preparation of SASD as was shown by circular dichroism. Furthermore, the in vitro CsA release profile kinetics was almost identical to the commercially available product Neoral®. This study presents the first in vivo proof-of-concept for a novel drug delivery system based on Poly-αβ-CD containing CsA, with SASD allowing for increased bioavailibility. The pharmacokinetic parameters of cyclosporine A from the spherical spray-dried dispersion formulation was demonstrated in a “rat” animal model. For comparison, the commercially available Neoral® was studied. Importantly, the pharmacokinetic parameters were improved by extending Tmax from 2 to 3 h after the oral administration in rats, and eventually preventing the enterohepatic circulation. All these results clearly demonstrate the improved pharmacokinetic parameters and enhanced bioavailability of CsA in the new developed drug delivery system. These data demonstrated the superiority of the newly developed Poly-αβ-CD formulation for oral administration of the poorly soluble CsA in vivo without altering its secondary structure. Poly-αβ-CD can be a very useful tool for the oral administration of poorly water-soluble drugs.

scholarly journals Pharmacokinetic Comparison of 20(R)- and 20(S)-Ginsenoside Rh1 and 20(R)- and 20(S)-Ginsenoside Rg3 in Rat Plasma following Oral Administration of Radix Ginseng Rubra and Sheng-Mai-San Extracts

2017 ◽  
Vol 2017 ◽  
pp. 1-10 ◽  
Author(s):  
Xiaomei Fan ◽  
Yan Xu ◽  
Danni Zhu ◽  
Yibing Ji
Keyword(s):  
Oral Administration ◽  
Rat Plasma ◽  
Pharmacokinetic Parameters ◽  
Spectrometric Method ◽  
Pharmacokinetic Studies ◽  
Mass Spectrometric Method ◽  
Ginsenoside Rg3 ◽  
Radix Ginseng

Ginsenosides Rh1 and Rg3, as the main bioactive components from Ginseng, are effective for prevention and treatment of cardiovascular diseases. Sheng-Mai-San (SMS), a classical complex prescription of traditional Chinese medicines, is composed of Radix Ginseng Rubra, Fructus Schisandrae, and Radix Ophiopogonis. In this research, a sensitive and specific liquid chromatography-mass spectrometric method was developed and validated for stereoselective determination and pharmacokinetic studies of 20(R)- and 20(S)-ginsenoside Rh1 and 20(R)- and 20(S)-ginsenoside Rg3 epimers in rat plasma after oral administration of Radix Ginseng Rubra or SMS extracts. The main pharmacokinetic parameters including Tmax, Cmax, t1/2, and AUC were calculated by noncompartment model. Compared with Radix Ginseng Rubra, SMS could significantly increase the content of ginsenosides Rh1 and Rg3 in the decocting process. Ginsenosides Rh1 and Rg3 following SMS treatment displayed higher Cmax, AUC(0–t), and AUC0–∞ and longer t1/2 and tmax except for 20(R)-Rh1 in rat plasma. The results indicated SMS compound compatibility could influence the dissolution in vitro and the pharmacokinetic behaviors in vivo of ginsenosides Rh1 and Rg3, suggesting pharmacokinetic drug-drug interactions between ginsenosides Rh1 and Rg3 and other ingredients from Fructus Schisandrae and Radix Ophiopogonis. This study would provide valuable information for drug development and clinical application of SMS.

scholarly journals Pharmacological Properties of a New Antimalarial Bisthiazolium Salt, T3, and a Corresponding Prodrug, TE3

2005 ◽  
Vol 49 (9) ◽  
pp. 3631-3639 ◽  
Author(s):  
Olivier Nicolas ◽  
Delphine Margout ◽  
Nicolas Taudon ◽  
Sharon Wein ◽  
Michèle Calas ◽  
...  
Keyword(s):  
Oral Administration ◽  
Antimalarial Activity ◽  
Plasma Concentrations ◽  
Intraperitoneal Administration ◽  
Absolute Bioavailability ◽  
Pharmacokinetic Parameters ◽  
Pharmacological Properties ◽  
Mean Values

ABSTRACT A new approach to malarial chemotherapy based on quaternary ammonium that targets membrane biogenesis during intraerythrocytic Plasmodium falciparum development has recently been developed. To increase the bioavailability, nonionic chemically modified prodrugs were synthesized. In this paper, the pharmacological properties of a bisthiazolium salt (T3) and its bioprecursor (TE3) were studied. Their antimalarial activities were determined in vitro against the growth of P. falciparum and in vivo against the growth of P. vinckei in mice. Pharmacokinetic evaluations were performed after T3 (1.3 and 3 mg/kg of body weight administered intravenously; 6.4 mg/kg administered intraperitoneally) and TE3 (1.5 and 3 mg/kg administered intravenously; 12 mg/kg administered orally) administrations to rats. After intraperitoneal administration, very low doses offer protection in a murine model of malaria (50% efficient dose [ED50] of 0.2 to 0.25 mg/kg). After oral administration, the ED50 values were 13 and 5 mg/kg for T3 and TE3, respectively. Both compounds exerted antimalarial activity in the low nanomolar range. After TE3 administration, rapid prodrug-drug conversion occurred; the mean values of the pharmacokinetic parameters for T3 were as follows: total clearance, 1 liter/h/kg; steady-state volume of distribution, 14.8 liters/kg; and elimination half-life, 12 h. After intravenous administration, T3 plasma concentrations increased in proportion to the dose. The absolute bioavailability was 72% after intraperitoneal administration (T3); it was 15% after oral administration (TE3). T3 plasma concentrations (8 nM) 24 h following oral administration of TE3 were higher than the 50% inhibitory concentrations for the most chloroquine-resistant strains of P. falciparum (6.3 nM).

scholarly journals The Use of Capsule Endoscopy to Determine Tablet Disintegration In Vivo

Pharmaceutics ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 498
Author(s):  
Lasse I. Blaabjerg ◽  
Li Fan ◽  
Xiaoli Chen ◽  
Philip J. Sassene
Keyword(s):  
Oral Administration ◽  
Capsule Endoscopy ◽  
Oral Dosage ◽  
Test Material ◽  
Pharmacokinetic Data ◽  
Actual Behavior ◽  
In Vitro Methods ◽  
Tablet Disintegration

The preferred delivery route for drugs targeted for systemic effect is by oral administration. Following oral administration, a solid dosage form must disintegrate and the drug dissolve, thereafter permeating the intestinal mucosa. Several different in vitro methods are used to investigate these processes, i.e., disintegration tests, dissolution tests, and permeability models. However, the actual behavior of oral dosage forms in the environment of the gastro-intestinal tract is not very well elucidated using these conventional methods. In this study, the use of capsule endoscopy to determine tablet disintegration in vivo was assessed. Panadol and Panadol Rapid (acetaminophen/paracetamol) were used as the test material. The in vivo tablet disintegration behavior in beagle dogs was assessed by the use of capsule endoscopy. The in vitro tablet disintegration behavior was assessed using the European Pharmacopeia (Ph. Eur.) disintegration test. The study showed that the in vivo disintegration times of Panadol and Panadol Rapid were 24.7 and 16.5 min, respectively, when determined by capsule endoscopy, which corresponded to the pharmacokinetic data. By contrast, the in vitro disintegration times of the same formulations were 5.5 and 4.0 min, respectively, when determined by the Ph. Eur. disintegration test. In conclusion, capsule endoscopy can be used to determine the in vivo tablet disintegration behavior. By contrast, the in vitro methods appear to not be predictive of the disintegration behavior in vivo but may be used to rank the order the formulations with respect to disintegration time.

Effects of Unfractionated and Low Molecular Weight Heparins on Platelet Thromboxane Biosynthesis “In Vivo”

1994 ◽  
Vol 72 (06) ◽  
pp. 942-946 ◽  
Author(s):  
Raffaele Landolfi ◽  
Erica De Candia ◽  
Bianca Rocca ◽  
Giovanni Ciabattoni ◽  
Armando Antinori ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Unfractionated Heparin ◽  
Low Molecular Weight Heparin ◽  
Primary Source ◽  
In Vivo Studies ◽  
Low Molecular Weight ◽  
Heparin Administration ◽  
To Receive

SummarySeveral “in vitro” and “in vivo” studies indicate that heparin administration may affect platelet function. In this study we investigated the effects of prophylactic heparin on thromboxane (Tx)A2 biosynthesis “in vivo”, as assessed by the urinary excretion of major enzymatic metabolites 11-dehydro-TxB2 and 2,3-dinor-TxB2. Twenty-four patients who were candidates for cholecystectomy because of uncomplicated lithiasis were randomly assigned to receive placebo, unfractionated heparin, low molecular weight heparin or unfractionaed heparin plus 100 mg aspirin. Measurements of daily excretion of Tx metabolites were performed before and during the treatment. In the groups assigned to placebo and to low molecular weight heparin there was no statistically significant modification of Tx metabolite excretion while patients receiving unfractionated heparin had a significant increase of both metabolites (11-dehydro-TxB2: 3844 ± 1388 vs 2092 ±777, p <0.05; 2,3-dinor-TxB2: 2737 ± 808 vs 1535 ± 771 pg/mg creatinine, p <0.05). In patients randomized to receive low-dose aspirin plus unfractionated heparin the excretion of the two metabolites was largely suppressed thus suggesting that platelets are the primary source of enhanced thromboxane biosynthesis associated with heparin administration. These data indicate that unfractionated heparin causes platelet activation “in vivo” and suggest that the use of low molecular weight heparin may avoid this complication.

Neutralization of a Low Molecular Weight Heparin (LHN-1) and Conventional Heparin by Protamine Sulfate in Rats

1986 ◽  
Vol 56 (03) ◽  
pp. 318-322 ◽  
Author(s):  
V Diness ◽  
P B Østergaard
Keyword(s):  
Molecular Weight ◽  
Low Molecular Weight Heparin ◽  
Thrombus Formation ◽  
Experimental Models ◽  
Protamine Sulfate ◽  
Low Molecular Weight ◽  
Antithrombotic Effect ◽  
Higher Doses

SummaryThe neutralization of a low molecular weight heparin (LHN-1) and conventional heparin (CH) by protamine sulfate has been studied in vitro and in vivo. In vitro, the APTT activity of CH was completely neutralized in parallel with the anti-Xa activity. The APTT activity of LHN-1 was almost completely neutralized in a way similar to the APTT activity of CH, whereas the anti-Xa activity of LHN-1 was only partially neutralized.In vivo, CH 3 mg/kg and LHN-1 7.2 mg/kg was given intravenously in rats. The APTT and anti-Xa activities, after neutralization by protamine sulfate in vivo, were similar to the results in vitro. In CH treated rats no haemorrhagic effect in the rat tail bleeding test and no antithrombotic effect in the rat stasis model was found at a protamine sulfate to heparin ratio of about 1, which neutralized APTT and anti-Xa activities. In LHN-1 treated rats the haemorrhagic effect was neutralized when APTT was close to normal whereas higher doses of protamine sulfate were required for neutralization of the antithrombotic effect. This probably reflects the fact that in most experimental models higher doses of heparin are needed to induce bleeding than to prevent thrombus formation. Our results demonstrate that even if complete neutralization of APTT and anti-Xa activities were not seen in LHN-1 treated rats, the in vivo effects of LHN-1 could be neutralized as efficiently as those of conventional heparin. The large fall in blood pressure caused by high doses of protamine sulfate alone was prevented by the prior injection of LHN-1.

The Application of the Cold Atmospheric Plasma-Activated Solutions in Cancer Treatment

2018 ◽  
Vol 18 (6) ◽  
pp. 769-775 ◽  
Author(s):  
Dayun Yan ◽  
Jonathan H. Sherman ◽  
Michael Keidar
Keyword(s):  
Cancer Treatment ◽  
Atmospheric Plasma ◽  
Current Status ◽  
Cold Atmospheric Plasma ◽  
Anti Cancer ◽  
Long Time ◽  
Key Topics ◽  
The Common

Background: Over the past five years, the cold atmospheric plasma-activated solutions (PAS) have shown their promissing application in cancer treatment. Similar as the common direct cold plasma treatment, PAS shows a selective anti-cancer capacity in vitro and in vivo. However, different from the direct cold atmospheric plasma (CAP) treatment, PAS can be stored for a long time and can be used without dependence on a CAP device. The research on PAS is gradually becoming a hot topic in plasma medicine. Objectives: In this review, we gave a concise but comprehensive summary on key topics about PAS including the development, current status, as well as the main conclusions about the anti-cancer mechanism achieved in past years. The approaches to make strong and stable PAS are also summarized.

Novel concatameric heparin-binding peptides reverse heparin and low-molecular-weight heparin anticoagulant activities in patient plasma in vitro and in rats in vivo

Blood ◽  
2004 ◽  
Vol 103 (4) ◽  
pp. 1356-1363 ◽  
Author(s):  
Barbara P. Schick ◽  
David Maslow ◽  
Adrianna Moshinski ◽  
James D. San Antonio
Keyword(s):  
Molecular Weight ◽  
Low Molecular Weight Heparin ◽  
Tandem Repeats ◽  
Factor Xa ◽  
Low Molecular Weight ◽  
Heparin Binding ◽  
High Affinity ◽  
Binding Peptides

Abstract Patients given unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH) for prophylaxis or treatment of thrombosis sometimes suffer serious bleeding. We showed previously that peptides containing 3 or more tandem repeats of heparin-binding consensus sequences have high affinity for LMWH and neutralize LMWH (enoxaparin) in vivo in rats and in vitro in citrate. We have now modified the (ARKKAAKA)n tandem repeat peptides by cyclization or by inclusion of hydrophobic tails or cysteines to promote multimerization. These peptides exhibit high-affinity binding to LMWH (dissociation constant [Kd], ≈ 50 nM), similar potencies in neutralizing anti–Factor Xa activity of UFH and enoxaparin added to normal plasma in vitro, and efficacy equivalent to or greater than protamine. Peptide (ARKKAAKA)3VLVLVLVL was most effective in all plasmas from enoxaparin-treated patients, and was 4- to 20-fold more effective than protamine. Several other peptide structures were effective in some patients' plasmas. All high-affinity peptides reversed inhibition of thrombin-induced clot formation by UFH. These peptides (1 mg/300 g rat) neutralized 1 U/mL anti–Factor Xa activity of enoxaparin in rats within 1 to 2 minutes. Direct blood pressure and heart rate measurements showed little or no hemodynamic effect. These heparin-binding peptides, singly or in combination, are potential candidates for clinical reversal of UFH and LMWH in humans.

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