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Biomedical subjects

C Caranobe

Publications and source records attributed to C Caranobe.

At least 37 records · Page 2Linked to original sources
PubMed1989

Pharmacokinetics of heparin and related polysaccharides.

The pharmacodynamic profile of standard heparin (SH), a low molecular weight derivative (CY 216) and of dermatan sulfate (DS), a new potential antithrombotic drug, was investigated in the rabbit over a large range of doses. After bolus i.v. injection of low doses, the biological activity of SH disappeared exponentially; however, its half-life was prolonged when the dose injected increased, and over 158 micrograms/kg (100 anti-factor Xa U/kg) the biological activity disappeared as a concave-convex curve. CY 216 disappeared more slowly than SH at low doses but faster than SH at higher doses. More than 90% of the DS biological activity present 1 minute after the i.v. injection disappeared exponentially without dose-dependent effects. Increasing doses of the three drugs were then delivered for 5 h under continuous infusions. Below 500 micrograms/kg/h the DS and CY 216 plateau concentrations were higher than that of SH while above this dose the SH concentration was higher than that of DS and CY 216. These observations may be explained by the results of pharmacokinetics experiments where 125I-labeled compounds were delivered by bolus i.v. injection in association with increasing doses of their unlabeled counterparts. For SH there was a 10-fold difference between the half-life of the lower dose (32 micrograms/kg or 5 anti-factor Xa U/kg) and that of the higher dose (3200 micrograms/kg); it was demonstrated that the half-life of SH continuously shortened as its plasma concentration decreased. In contrast the CY 216 and DS half-lives were very close, independent of the dose delivered, and therefore longer than that of SH at low doses and shorter than that of SH at higher doses. The renal contribution to the clearance of SH, CY 216, and DS was also investigated by injecting a low dose (150-200 micrograms/kg) and a 10 times higher dose to sham-operated or binephrectomized animals: renal function is critical for the elimination of the three compounds from the blood except for SH at low doses. These observations are promising for the development of DS and may have clinical implications.

Animals↗
PubMed1988

Further studies on the mechanisms for the antithrombotic effects of sulfated polysaccharides in rabbits.

A recent study (Fernandez et al., Thromb. Haemostas. 1987; 57: 286-93) demonstrated that when rabbits were injected with the minimum weight of a variety of glycosaminoglycans required to inhibit tissue factor-induced thrombus formation by approximately 80%, exogenous thrombin was inactivated approximately twice as fast in the post-treatment plasmas as the pre-treatment plasmas. In this study, we investigated the relationship between inhibition of thrombus formation and the extent of thrombin inhibition ex vivo. We also investigated the relationship between inhibition of thrombus formation and inhibition of prothrombin activation ex vivo. Four sulfated polysaccharides (SPS) which influence coagulation in a variety of ways were used in this study. Unfractionated heparin and the fraction of heparin with high affinity to antithrombin III potentiate the antiproteinase activity of antithrombin III. Pentosan polysulfate potentiates the activity of heparin cofactor II. At less than 10 micrograms/ml of plasma, all three SPS also inhibit intrinsic prothrombin activation. The fourth agent, dermatan sulfate, potentiates the activity of heparin cofactor II but fails to inhibit intrinsic prothrombin activation even at concentrations which exceed 60 micrograms/ml of plasma. Inhibition of thrombus formation by each sulfated polysaccharides was linearly related to the extent of thrombin inhibition achieved ex vivo. These observations confirm the utility of catalysis of thrombin inhibition as an index for assessing antithrombotic potential of glycosaminoglycans and other sulfated polysaccharides in rabbits. With the exception of pentosan polysulfate, there was no clear relationship between inhibition of thrombus formation and inhibition of prothrombin activation ex vivo.

Animals↗
PubMed1988

Effects of increased sulfation of dermatan sulfate on its in vitro and in vivo pharmacological properties.

The in vitro and in vivo pharmacological properties of two oversulfated dermatan sulfate (DS) derivatives, S-DS1 and S-DS2, containing 2 and 3.7 sulfate groups/disaccharide unit respectively were compared to those of the parent DS (1 sulfate group/disaccharide unit). In a purified system the ability of S-DS1 and of S-DS2 to catalyse thrombin inhibition by heparin cofactor II was increased by ten- and seventeen-fold respectively. These compounds also had more potent anticoagulant activities in the activated partial thromboplastin time and the thrombin clotting time assays. Plasma immunodepleted in antithrombin III, heparin cofactor II and both cofactors allowed it to be demonstrated that these enhanced anti-coagulant activities were partly (S-DS1) or totally (S-SD2) independent of any plasma cofactors. In spite of these enhanced anticoagulant activities in vitro the oversulfated derivatives did not exhibit an increased antithrombotic activity in a thromboplastin Wessler type model. Moreover, at the doses investigated, S-DS2 had no antithrombotic effect. The influence of oversulfation on the pharmacokinetic pattern of DS was also investigated. As reported for unfractionated heparin, the biological activities generated after IV injection of high doses of S-DS1 and S-DS2 disappeared according to a concave-convex pattern. This may result from the higher affinities of S-DS1 and of S-DS2 toward endothelial cells in comparison with that of DS.

Animals↗
PubMed1988

Standard heparin enhances the antithrombotic activity of dermatan sulfate in the rabbit but CY 216 does not.

Standard heparin (SH) and dermatan sulfate (DS) two glycosaminoglycans with different pharmacological targets are effective antithrombotic agents in the rabbit. We have investigated the antithrombotic activity of the association DS plus SH. It was found that doses as low as 25 micrograms/kg for DS and 10 micrograms/kg for SH were ineffective when injected separately but generated a high and significant antithrombotic activity when injected together. These results were confirmed when higher doses of each compound were delivered in association. Further experiments were performed to determine if the enhancement of the antithrombotic activity of DS by HS resulted from its anti-factor IIa or anti-factor Xa activity or from its moiety without affinity to AT III. A low molecular weight heparin (CY 216) with an anti-factor Xa/anti-factor IIa ratio of 5, the synthetic pentasaccharide bearing the minimum binding sequence to antithrombin III, and a low affinity fraction of SH to AT III did not increase the antithrombotic activity of DS; in contrast a high affinity fraction of SH to AT III had the same effect than SH. We conclude that the enhancement of the antithrombotic activity of DS by SH mainly results from its anti-factor IIa activity.

Animals↗
PubMed1988

Pharmacokinetics of dermatan sulfate in the rabbit after intravenous injection.

To 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 micrograms/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 micrograms/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.

Animals↗
PubMed1987

Antithrombotic and bleeding effects of a new synthetic direct thrombin inhibitor and of standard heparin in the rabbit.

This study reports on the anticoagulant, antithrombotic and bleeding effects of a new synthetic direct thrombin inhibitor (SDTI) in comparison with standard heparin (SH). The anticoagulant effect was determined with the thrombin clotting time (TCT) and the activated partial thromboplastin time (APTT). SDTI was more potent than SH in prolonging the TCT, but as potent as SH in prolonging the APTT. The antithrombotic effect was determined using a modified Wessler model in the rabbit, either 30 min after a continuous IV infusion of increasing doses or at various times after a single SC injection (20 mg/kg). After continuous IV infusion of 187 micrograms/kg/h of SDTI and of 60 micrograms/kg/h of SH, significant thrombus prevention effects were obtained (59 and 57% respectively). Increasing the dose of SDTI up to 3000 micrograms/kg/h did not significantly improve the antithrombotic effect. After SC injection, a significant antithrombotic effect was observed for 12 h with SDTI but for more than 24 h with SH. The bleeding effect was studied using the rabbit ear model 15 min after a continuous infusion of 7.5 and 15 mg/kg/h: the amounts of blood loss were dose-dependent and comparable for SDTI and SH. These studies also indicated that SDTI possesses a considerable shorter half-life in comparison with SH. Accordingly, the ex vivo concentrations generated after continuous IV infusion or SC injection of the same dose were higher for SH than for the SDTI.

Animals↗
PubMed1987

Evidence for a saturable mechanism of disappearance of standard heparin in rabbits.

This work demonstrates that after bolus intravenous injection standard heparin (SH) disappearance results from the combination of a saturable and a non saturable mechanism. Pharmacokinetics and pharmacodynamics of SH were studied by measuring the disappearance of increasing doses (5 - 500 anti-factor Xa U/kg) of 125I-heparin and of its biological effects. CPM curves allowed to determine the half lives of heparin according to the dose injected. The half lives were clearly dose dependent and reached a plateau over 100 anti-factor Xa U/kg. The complex curve which describes the amount of heparin cleared per time unit after any given dose has been resolved into its two components reflecting a saturable and a non saturable mechanism of disappearance. For the doses less than 100 anti-factor Xa U/kg the saturable mechanism was preeminent and the anti-factor Xa activity disappearance followed an exponential pattern; for the doses less than 100 anti-factor Xa U/kg the contribution of the non saturable mechanism becomes more important and the anti-factor Xa activity disappearance followed a concave-convex pattern. Further experiments showed that the heparin half life shortened as the circulating anti-factor Xa activity decreased; this phenomenon may explain the concave-convex pattern of the curve of the anticoagulant effect observed after injection of large doses of SH.

Animals↗
PubMed1987

The disappearance of a low molecular weight heparin fraction (CY 216) differs from standard heparin in rabbits.

In previous studies, we have reported that standard heparin (SH) was cleared by two mechanisms, a saturable mechanism which predominated at low doses (less than 100 anti-factor Xa U/kg) and a non-saturable mechanism which predominated at higher doses, when the first mechanism became saturated. In this study, we examined the importance of these two mechanisms in the disappearance of a low molecular weight heparin fraction (LMWH) (CY 216), by comparing the pharmacokinetics and the pharmacodynamics of a wide range of doses of SH and CY 216 (1.5 to 500 anti-factor Xa U/kg). Pharmacokinetics was measured as the disappearance of 125I-radiolabelled SH or CY 216. Pharmacodynamics was measured as the disappearance of the anti-factor Xa activity of SH and CY 216. We found that the saturable mechanism contributed little to the disappearance of CY 216 and that it was cleared predominantly by the non-saturable mechanism at all doses tested. Thus, at low doses (less than 100 anti-factor Xa U/kg), SH was cleared more rapidly than CY 216, whereas at higher doses, CY 216 was cleared more rapidly than SH. We conclude that the mechanism of disappearance of LMWH's differ significantly from those of SH, and that this difference may explain the apparent prolonged anticoagulant activity of LMWH's within the therapeutic range doses.

Animals↗
PubMed1986

Heparin fractions with high and low affinities to antithrombin III are cleared at different rates.

The clearance characteristics of standard heparin (SH) and its fractions with high and low affinity to antithrombin III (HAH and LAH respectively) were studied by injecting 125I-labelled SH, HAH and LAH intravenously into the rabbits in increasing doses. Serial blood samples were then collected from an indwelling cannula for measurement of clearance, based both on radioactivity and anticoagulant activity. For equivalent weights injected, the radioactivity of HAH was cleared more slowly from the circulation than that of either SH or LAH. The radioactivity of SH, in turn, was cleared more slowly than that of LAH. The clearance of HAH, measured both by radioactivity and by anticoagulant activity were similar, whereas the clearance of the radioactivity of SH was more rapid than its anticoagulant activity (i.e. anti-factor Xa activity). These observations suggest that the radioactivity clearance curves of SH reflect a "net" estimation of the more complex clearance curves of the different heparin moieties whereas the anticoagulant clearance curves of SH reflects the clearance of the anticoagulant activity of a specific heparin fraction, in this case, the clearance of the anti-factor Xa activity of HAH. These differences suggest that the HAH:LAH ratio is, at any given time, greater in vivo than the same ratio measured in vitro.

Animals↗
PubMed1986

[Macrothrombocytosis and idiopathic thrombocytopenic purpura: effect of anticoagulant and prior fixation on the determination of platelet volume using the Coulter system].

This study was designed to evaluate the importance of anticoagulants and of prior fixation on the Coulter Counter platelet size determination in macrothrombocytosis occurring in patients affected with an idiopathic thrombocytopenic purpura (ITP). Native blood was sampled either in an iso-osmotic glutaraldehyde fixative solution at 37 degrees C or in standard citrated or EDTA vacutainers. Platelet size increased from the fixed whole blood sample to the unfixed standard citrate and EDTA samples. There was a good correlation between the three determinations. Of the 23 ITP cases 10 presented large sized platelets both in citrated and in fixed whole blood samples; however 4 of these patients presented a platelet size in the normal range in the EDTA samples. These results show that citrated blood samples are preferable to EDTA samples for detecting an increased platelet size in ITP and that ITP macrothrombocytosis does not result from an abnormal hypervolumetric shape change occurring in vitro after sampling.

Anticoagulants↗
PubMed1985

Platelet regeneration time after aspirin ingestion and platelet survival time after labelling with 51chromium or 111indium oxine--a comparative study.

A simultaneous investigation of platelet regeneration time (PRT) based upon malondialdehyde (MDA) recovery after a single oral intake of 500 mg of aspirin and of platelet survival time (PST) after labelling with 51chromium or 111indium oxine was performed in 25 cancerous patients. A pilot study conducted with 9 healthy volunteers demonstrated that the MDA assay was highly reproducible and specific for the platelet cycloxygenase activity. The pattern of MDA recovery after aspirin ingestion was linear in the healthy volunteers and in the patients presenting both a normal and an accelerated platelet turnover. PST were calculated using the four mathematical models recommended by the International Committee for Standardization in Hematology; the best fit was given by the multiple hit model in 22 cases and by the linear regression model in 3 cases. The mean results obtained in the patients investigated with the 51chromium were consistently shorter than those obtained in the patients investigated with the 111indium oxine while the mean PRT were almost identical in the two groups. An excellent correlation between PRT and PST was observed after 111indium oxine labelling and using the weighted mean method for PST determination. These results suggest that the 111indium oxine technique is a better method for platelet labelling and that the results provided by the weighted mean method reflect more closely the in vivo platelet turnover than those provided by the multiple hit model.

Adult↗
PubMed1985

Platelet alpha 2 adrenoceptors in Parkinson's disease: decreased number in untreated patients and recovery after treatment.

[3H]-yohimbine binding sites were quantified in platelets from Parkinsonians with no clinical signs of dysautonomia. Never-treated Parkinsonians had a lower specific binding than control subjects. This alteration was associated with decreased epinephrine-induced platelet aggregation. Treatment with dopaminergic agents induced a significant increment of [3H]-yohimbine binding sites. These results show that Parkinson's disease is associated with a reduced number of peripheral alpha 2 adrenoceptors and that dopaminergic agents induce partial recovery.

Aged↗