Prophylactic low dose heparin anticoagulant therapy in patients with spinal cord injuries: a retrospective study.

A retrospective study was performed of 100 consecutive acute traumatic spinal injury patients with neurological deficit admitted to the Yorkshire regional spinal injuries centre prior to May 1990. Ninety-seven of these patients received prophylactic low dose subcutaneous heparin and 3 patients were excluded because of noted complications. Twenty-six patients developed thromboembolic complications. Apart from the fact that acute spinal cord injury patients are considered to be in an hypercoaguable state, the occurrence of deep vein thrombosis/pulmonary embolism (DVT/PE) in our study, even though these patients were on prophylactic low dose subcutaneous heparin, was related to delay in transfers, operative intervention, level of spinal cord injury and was possibly due to loss of some amount of heparin solution from the prefilled syringe during removal of air bubbles prior to the subcutaneous heparin injection.     

Fibrinolytic and anticoagulant activity after a single subcutaneous administration of a low dose of heparin or a low molecular weight heparin-dihydroergotamine combination

The anticoagulant and potential profibrinolytic effect of a combination of low molecular weight heparin with dihydroergotamine (LMWH-DHE) and of unfractionated heparin was studied in eight healthy volunteers. Each volunteer received a subcutaneous injection of either LMWH-DHE (1,500 U anti-Xa of LMWH + 0.5 mg DHE), unfractionated heparin (5,000 IU) or of placebo (saline) between 7 and 8 h in the morning on three different occasions. Anti-Xa activity, and fibrinolytic activity measured by the euglobulin clot lysis time (ECLT) and by the fibrin plate assay were determined before and at different times after administration of the three substances. Anti-Xa activity in plasma reached a maximum four hours after injection of both LMWH-DHE and unfractionated heparin. LMWH-DHE showed a better bioavailability when compared to unfractionated heparin; the anti-Xa activity peak was two and a half fold higher after LMWH-DHE despite injection of a three fold lower dose of anti-Xa units. The half-life of anti-Xa activity was approximately 4 hours for LMWH-DHE but only 90 min for unfractionated heparin. The fibrinolytic activity measured by ECLT as well as by fibrin plate assay, showed a significant increase during the day reaching a peak 8-12 h after injection regardless of the product administered (including the placebo). The profile of the diurnal fibrinolytic activity curve was identical for all three substances. The increase in fibrinolytic activity, observed after administration of LMWH-DHE or unfractionated heparin, was therefore not due to these drugs but reflected the circadian physiological fluctuation of fibrinolysis.     

Diurnal variation of pain perception and heart rate in the human tourniquet pain model in healthy volunteers

The diurnal variation of pain threshold was studied in 13 healthy volunteers (age: 21 - 27 ys) using the tourniquet pain model. A tourniquet was inflated above systolic blood pressure for 1 minute and pain scores and heart rate were recorded at 0.5, 1.0, 1.5 and 2.0 minutes. The test was repeated during a study day at 6.00 h, 12.00 h, 18.00 h and 24.00 h. Significant differences of pain scores between clocktimes were found 1 minutes after inflation and after 1.5 minutes with regard to heart rate. Generally, the highest pain scores were found at 24.00 h.     

Bleeding times in rats treated with heparin, heparin fragments of high and low anticoagulant activity and chemically modified heparin fragments of low anticoagulant activity

A template bleeding time study in the rat was undertaken to see if it is possible to correlate bleeding times with the molecular weight, anticoagulant activity or chemical composition of heparin or heparin-derived compounds. Heparin from porcine intestinal mucosa (PM-heparin) and from bovine lung (BL-heparin) as well as heparin fragments from these sources were compared. Heparin fragments of low anticoagulant activity were prepared by affinity chromatography on immobilized antithrombin as well as by chemical modification. A heparin fragment of high affinity for antithrombin (HA-fragment) caused a marked and dose-dependent increase in bleeding time while the corresponding heparin fragment with low affinity for antithrombin (LA-fragment) had a marginal and non-dose dependent effect on the bleeding time. Similar results were also obtained with PM-heparin with high and low affinity for antithrombin. A high anti-FXa activity was not always correlated with a marked bleeding tendency. Provided that a fragment was devoid of activated partial thromboplastin time (APTT) activity, it was not possible to provoke a bleeding time of 20 min or longer, although the compound was administered at a dose of 1,088 U/kg (anti-FXa activity). On the other hand, a N-acetylated chemically oversulphated heparin fragment, with a very low anti-FXa activity (1 U/mg) and with an APTT activity of 34 U/mg, caused a bleeding time of 20 min or longer in 70% of the animals after injection of the same number of APTT units, 1,088 U/kg. These data indicate that the APTT activity is a better and more sensitive indicator of the bleeding than is the anti-FXa activity.     

The effect of prophylaxis with low dose heparin on blood coagulation parameters. A double blind study in connection with transvesical prostatectomy.

Heparin was administered subcutaneously 5.000 IU twice daily using a double blind method to ten of twenty-one patients undergoing transvesical prostatectomy. Platelet count, APTT, throbin time, Reptilase time, Normotest, fibrinogen, Factor-VIII, ethanol gelation test, antithrombin III, fibrinolytic degradation products, alpha1-antitrypsin and alpha2-macroglobulin were studied pre- and postoperatively up to the 10th postoperative day. Statistical analysis of parameters of blood coagulation and fibrinolysis showed no significant difference between the two groups. The mechanism by which low dose heparin exerts its thromboprophylactic effect could not be elucidated from the study of the investigated parameters. The laboratory data gave no indication to a possible increased risk of postoperative hemorrhage.     

Cerebral venous system mechanics during a constant infusion in subarachanoid space: a model study.

A model has been developed to explain the development of stress under a constant infusion of fluid into the subarachanoid space. When the regulatory mechanism operates, the infused fluid is accommodated by the venous system and hence the tissue 'give' mechanism is under minimal stress. The necessity of maintaining a constant blood flow causes the blood vessel to dilate at higher CSF pressures. This puts the tissue 'give' mechanism under dual pressures, since it has to make room for the expanding ventricle as well as the dilating venous system. The theoretical model developed has been validated by experimental observations.     

Circulating activities during constant infusion of heparin or a low molecular weight derivative (enoxaparine): failure to demonstrate any circadian variations

We compared in six patients successively treated with an unfractionated heparin (UFH) and a low molecular weight heparin (LMWH) the variations in plasma anti-Xa activity, measured in a chromogenic assay, during a 36 h constant infusion. The values varied in a wider range during UHF infusion, but remained in the therapeutic range except once in one patient. No circadian rhythm could be demonstrated in our six patients. LMWH infusion yielded very constant anti-Xa circulating activities. In both cases, there were no significant modifications of three proteins with high heparin affinity (antithrombin III, heparin cofactor II, histidine-rich glycoprotein). Our results suggest that the circadian rhythm of the biological activities previously observed in patients treated with constant heparin infusion using clotting method is due to other factors than heparin itself.     

Pharmacokinetics of a low molecular weight heparin, Logiparin, after intravenous and subcutaneous administration to healthy volunteers

In six healthy volunteers we have estimated the pharmacokinetic parameters of the anti factor Xa (AXa) and anti factor IIa (AIIa) activities of a LMW heparin, Logiparin. For the AXa the following parameters were estimated in a 1-compartment model (mean and 95% confidence limits in brackets): elimination half life 82 minutes (60–127 min), absorption half life (s.c.inj.) 200 minutes (137–368 min), bioavailability 90% (24–156 %), and apparent volume of distribution 3.9 1 (3.1–5.2 1). The plasma activity was linearly correlated to the dose given and to the body weight of the volunteer. For the AIIa the parameters estimated in a 1-compartment model were: elimination half life 71 minutes (52–115 min), absorption half life 257 minutes (133–3442 min), bioavailability 67% (44–90 %), and apparent volume of distribution 10.1 1 (7.2–16.7 1). The plasma activity was dependent on dose and body weight but it also seemed to be influenced by individual factors. This study shows that the absorption rate is the rate limiting factor and the explanation for the long lasting effect of this LMW heparin after subcutaneous injection. The slow absorption rate and the high bioavailability are probably the major advantages of LMW heparins compared to conventional heparin.     

The effect of a single low dose of trihexyphenidyl on memory functioning in the healthy elderly.

Medications with anticholinergic properties, when taken at therapeutic doses, are known to adversely affect memory functioning in young adults and the elderly. However, their impact at lower doses in geriatric persons has been less thoroughly studied. We investigated the impact of a single 2-mg dose of trihexyphenidyl on memory functioning in 20 healthy elderly subjects using a within-subjects, double-blind comparison with a placebo. Memory functioning was evaluated using subtests of the Wechsler Memory Scale. Subjects also rated the perceived impact of medication on their performance following memory testing. Results indicated that the single 2-mg dose of trihexyphenidyl produced impaired performance on measures of immediate and half-hour delayed recall of complex verbal and visual material when compared to the placebo condition. However, differences were not found on several other memory measures, including general orientation, attention-concentration, and learning of word associations. The significance of these selective memory deficits and suggestions regarding future research are discussed.     

Effects of an enzymatically depolymerized heparin as compared with conventional heparin in healthy volunteers

A low molecular weight heparin (LMW-heparin) with a mean molecular weight of 4900 dalton was prepared by controlled enzymatic depolymerization of conventional porcine mucosal heparin. The effects of 2,500, 5,000 and 10,000 U (XaI; 29, 58 and 116 mg) on factor Xa inhibition (XaI), factor IIa inhibition (IIaI), APTT, AT III and platelet count were compared to those of 5,000 U (XaI; 26 mg) of conventional heparin given s.c. to 6 healthy volunteers. 5,000 U (XaI; 58 mg) of LMW-heparin was given i.v. A dose related response with regard to the XaI and the IIa-inhibitory activities with peak values at 4 hours after the s.c. injections was obtained. An increase of the XaI/IIaI ratio over the time after injection was seen only after i.v. administration of the LMW-heparin. The APTT was only slightly prolonged and remained within normal range after s.c. injection. AT III and platelet counts were unaffected. The biological half life of the LMW-heparin was 111 minutes if assayed by Xa inhibition, 76 minutes if assayed by IIa inhibition and 40 minutes if assayed by APTT. A strong correlation between the XaI activities obtained and body weight was seen, indicating that LMW-heparin should be administered individually according to body weight.     

Thrombin activity during hemodialysis; evaluated by the fibrinopeptide a assay. A comparison between a high and a low heparin dose regime.

Ten patients participated in this study which evaluated the effect of two heparin dose regimes, a high dose regime (mean dose 6750 IU) and a low dose regime (mean dose 3750 IU), on the thrombin activity, achieved during a 4-hour-dialysis. The thrombin activity was measured by use of the FPA assay. Heparin was administered as bolus dose followed by a constant rate infusion which was discontinued 1.5–2 hours prior to the end of the dialysis. Both dose regimes inhibited thrombin activity equally effectively as long as heparin was administered. In the high dose regime, the FPA levels remained unchanged until the end of the dialyses in all patients. In the low dose regime, six patients had the same FPA values at the end of the heparin infusion and at the end of the dialysis. In the remaining four patients much higher FPA levels were achieved at the end of the dialysis. No serious bleeding or clotting complications occurred, and all dialyses were uneventful.     

Study of low molecular weight heparin effect on the relation between anticoagulant activity and antithrombin III affinity.

Low molecular weight heparin (FR-860), and conventional unfractionated heparin (UF-heparin) were fractionated by rabbit antithrombin III (AT III)-Sepharose, and the effects of each affinity fraction on the coagulation and fibrinolytic activities were investigated. FR-860 was fractionated to no-affinity, low-affinity (LA) and high-affinity (HA) fractions, and UF-heparin to LA and HA fractions. The HA fractions showed higher activities regarding the prolongation of activated partial thromboplastin time, anti-factor Xa activity and antithrombin activity compared with those of LA. The HA and LA fractions exhibited the enhancement of heparin cofactor II (HC II) activity and fibrinolytic activity in a dose-dependent manner. These results suggest that the antithrombotic activity of FR-860 is exerted through AT III and other mechanism such as HC II-mediated system.     

Subcutaneous treatment of deep venous thrombosis with low molecular weight heparin. A dose finding study with LMWH-Novo

Treatment of deep venous thrombosis with low molecular weight heparin (LMWH-Novo, Logiparin) was carried out with two different doses of Logiparin, 75 XaI U/kg b.w. twice daily and 150 XaI U/kg b.w. once daily subcutaneously for 5 days. Simultaneously warfarin was given from the first day of heparin treatment. Mean age of the twenty patients was 65 years and one third was females. No serious side effects, hematomas, pulmonary emboli or signs of recurrent thrombosis occurred during treatment with either dose regime. Venografic assessment with Marder scoring one week after initiation of Logiparin treatment showed a slight not significant improvement apparent in 40 % of the patients. The activities of F-IIaI and F-XaI in the blood plasma were found to increase after injection of Logiparin. These two parameters seem to be the most suitable for monitoring the effect during treatment. For future studies on the therapeutic effect of Logiparin in deep venous thrombosis a single dose of 150 to 200 F-XaI activity per 24 hours seems to be most suitable.     

Cerebral venous system mechanics during a constant infusion in subarachanoid space: a model study

Abstract

A model has been developed to explain the development of stress under a constant infusion of fluid into the subarachanoid space. When the regulatory mechanism operates, the infused fluid is accommodated by the venous system and hence the tissue ‘give’ mechanism is under minimal stress. The necessity of maintaining a constant blood flow causes the blood vessel to dilate at higher CSF pressures. This puts the tissue ‘give’ mechanism under dual pressures, since it has to make room for the expanding ventricle as well as the dilating venous system. The theoretical model developed has been validated by experimental observations. [Neurol Res 1992; 4: 000-000]     

Safety assessment and pharmacodynamics of a novel ultra low molecular weight heparin (RO-14) in healthy volunteers--a first-time-in-human single ascending dose study

Introduction

RO-14 is a novel ultra low molecular heparin. The purpose of this study was to evaluate the safety and pharmacodynamic profile of RO-14 in healthy males.

Materials and methods

We conducted a two-stage, single-center, open-label, randomized study. Two cohorts of 6 volunteers were randomly assigned to 12 single, ascending subcutaneous doses (1750-19950 IU of anti-FXa activity) in an alternating crossover fashion. Safety was assessed by spontaneous/elicited adverse events, medical examination and laboratory tests. Anti-FXa activity and anti-FIIa activity were assessed throughout the 24 hours after dosing. Dose proportionality and linearity of the anti-FXa activity were evaluated.

Results

All doses were well tolerated and there were no bleeding events. At the lowest dose, anti-FXa activity A_max was 0.16 (± 0.02) IU/mL and AUC_0-24 was 1.11 (± 0.24) IU*h/mL, At the highest dose anti-FXa activity A_max was 1.67 (± 0.15) IU/mL; AUC_0-24 was 21.48 (± 4.46) IU*h/mL and t½ was 8.05 h. Mean T_max (all doses) was 2.86 (± 0.39) h. RO-14 showed proportional and linear pharmacodynamics [normalized A_max among doses (p = 0.594) and normalized AUC_0-24 (p = 0.092), correlations between A_max-dose (R² = 0.89, p < 0.001) and AUC_0-24-dose (R² = 0.86, p < 0.001)]. Anti-FIIa activity was below the detection limit (0.1 IU/ml) at all dose levels. No clinically significant changes were observed in the platelet count, APTT, PT, TT, fibrinogen and antithrombin.

Conclusions

In this phase I study, RO-14 exhibited a good safety profile, anti-FXa activity for either prophylaxis or treatment of venous thromboembolism, linear pharmacodynamics, a longer elimination half-life than currently marketed low molecular weight heparin and no anti-FIIa activity.     

Analgesic effect of tiapride in healthy volunteers

Twenty male volunteers, average age 23, were studied in the fasting state at a week interval in the morning between nine and ten a.m. A brachial blood pressure cuff was inflated to a pressure of 250 mmHg and the subject squeezed a hand dynamometer to half of maximum strength for two ten seconds periods. The subject then started to report his sensory experience every ten seconds for 15 minutes by pointing at a scale consisting of six categories from "nothing" to "extremely painful". The first trial was performed on all unmedicated subjects, the non dominating arm was used. The second trial was performed on the opposite arm, 45 minutes after oral double-blind randomized administration of a capsule containing either 1 g aspirin or 300 mg tiapride. The answers of the subjects were statistically analysed using paired comparisons tests. Results indicate that tiapride exerts a significant antalgic effect from the 6th minute to the end of the experiment when compared to the control (p less than 0.05 to p less than 0.01). Aspirin produces a similar antalgic effect which occurs earlier, after 4 minutes. The mechanism of the antalgic effect of tiapride has been attributed to the release of beta-endorphine produced by benzamide which is associated with a decrease in plasma dopamine and a parallel increase in prolactine.     

Diurnal periodicity of lateral asymmetries of the visual evoked potential in healthy volunteers

Visual evoked potential (VEP) was analyzed in 24 healthy male volunteers (age: 25-35 years) between 7.00 a.m. and 4.00 p.m. to evaluate possible diurnal variation in hemispheric differences of the response to a diffuse or 1 degree flash and checkerboard pattern-reversal (stimulation: binocular). VEP was recorded over O1-A1 and O2-A2, and 64 exposures were averaged during each session. After diffuse and 1 degree flash stimulation the amplitudes of early components (latencies less than 140 ms) were higher over the right hemisphere (O2-A2) than over the left (O1-A1) in the morning. These differences disappeared during the afternoon. Late components (latencies greater than 250 ms) exhibited higher amplitudes over the left than over the right hemisphere during the whole experiment. With checkerboard pattern-reversal stimulation such a time-dependent change in the amplitudes of VEP between both hemispheres was not measurable.