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Background Unfractionated heparin and its low molecular weight fragments possess antithrombotic properties, properties that are routinely exploited in coronary angioplasty (PTCA).Objectives In the setting of the REDUCE trial, a randomized, double-blind, multicentre trial, the occurrence of acute or early clinical events was compared in patients treated with either unfractionated heparin/placebo or low molecular weight heparin (reviparin).Methods and results Six hundred and twelve patients with native coronary artery obstructions randomized between unfractionated heparin/placebo and reviparin, were analysed. Baseline characteristics were similar in both groups. Using the intention-to-treat analysis, major acute or early events (myocardial infarction, re-PTCA, bypass surgery, death) occurred in 42 patients (7%), 29 in the control group and 13 in the treatment group (P=0·027). In order to develop a predictive model for the risk of early events following coronary balloon angioplasty, clinical as well as pre-PTCA and procedural characteristics were analysed. Thrombi at the treated lesion site (P=0·02), dissection (P<0·001), lesion type B2and C according to the NHLBI classification (P<0·001), diameter stenosis >50% post-PTCA (P<0·001), and length of stenosis >20mm (P=0·005) were significantly associated with the occurrence of acute events. By multiple logistic regression analysis, in which these variables and the treatment regimen were entered, dissection (P=0·042), diameter stenosis >50% (P<0·028) and lesion type B2and C (P=0·017) were found to be independently predictive of early adverse events. Bleeding complications were similar in the two treatment groups.Conclusions Reviparin, given in a very early stage of vascular injury, compares favourably with unfractionated heparin/placebo, by reducing abrupt closure and acute-phase adverse outcome following PTCA. With respect to the evaluated risk factors for acute events, the positive effect of reviparin on early adverse outcome after PTCA may be due to improved antithrombotic properties as compared to unfractionated heparin. [ABSTRACT FROM PUBLISHER]

Background: Unfractionated heparin and its low molecular fragments possess antiproliferative effects and have been shown to reduce neointimal smooth muscle cell migration and proliferation in response to vascular injury in experimental studies., Objectives: The specific objective of the REDUCE trial was to evaluate the effect of a low molecular weight heparin on the incidence and occurrence of restenosis in patients undergoing percutaneous transluminal coronary angioplasty., Methods: The REDUCE trial is an international prospective, randomized, double-blind, multicenter study. Twenty-six centers in Europe and Canada enrolled 625 patients with single lesion coronary artery obstructions suitable for PTCA. Three hundred and six patients received reviparin as a 7000 U bolus before PTCA followed by 10,500 U as an infusion over 24 hours and then twice a day 3500 U s.c. application for 28 days. The 306 patients in the control group received a bolus of 10,000 U unfractionated heparin followed by an infusion of 24,000 U over 24 hours. These patients then received 28 days of s.c. placebo injections. The primary endpoints were efficacy (defined as a reduction in the incidence of major adverse events, i.e., death, myocardial infarction, need for reintervention or bypass surgery), absolute loss of minimal luminal diameter, and incidence of restenosis during the observation period of 30 weeks after PTCA., Results: Using the intention-to-treat analysis for all patients, 102 patients (33.3%) of the reviparin group and 98 patients (32%) of the control group have reached a primary clinical endpoint (relative risk = 0.98; 95% confidence limit, 0.88-1.09; p = 0.707). Likewise, no difference in late loss of minimal luminal diameter was evident for either group. Acute events within 24 hrs occurred in 3.9% of the reviparin group and in 8.2% of the control group (relative risk = 0.49; 95% confidence limit, 0.26-0.92; p = 0.027) during or immediately after the initial procedure. In the control group, 8 major bleedings occurred, and in the reviparin group, 7 major bleeding complications were observed within 35 days after PTCA., Conclusions: Reviparin use during and after coronary angioplasty did not reduce the occurrence of major clinical events or the incidence of angiographic restenosis over 30 weeks.

The introduction of low-molecular-mass heparins (LMMHs) has added a new dimension to the prophylactic and therapeutic management of thromboembolic disorders. These agents are now globally accepted as drugs of choice for postsurgical prophylaxis of deep vein thrombosis (DVT). Currently, the LMMHs are being developed for various therapeutic and cardiovascular indications. Reviparin is an optimized LMMH prepared by controlled nitrous acid digestion of porcine mucosal heparin. This drug has been developed utilizing validated procedures and exhibits a relatively narrow molecular mass distribution in contrast to most other commercially available LMMHs. The specific activity in the anticoagulant assays is approximately 40 U/mg whereas the specific activity in amidolytic anti-Xa assays is approximately 100 anti-Xa U/mg. Reviparin is capable of producing dose- and time-dependent antithrombotic effects in animal models of thrombosis. Although ex vivo anticoagulant effects are initially observed at dosages that are antithrombotic, this agent has been found to produce sustained antithrombotic effects when ex vivo anticoagulant actions are not measurable. Repeated administration of this LMMH induces progressively stronger antithrombotic effects. This drug has also been found to release tissue factor pathway inhibitor (TFPI) following both intravenous (IV) and subcutaneous (SC) administration. The studies included in this article are designed to provide additional data on the molecular profile using new calibration methods and additional results on pharmacologic studies. In particular, the release of TFPI following IV and SC administration to nonhuman primates is described. The effect of repeated administration of Reviparin mimicking the postsurgical prophylaxis of DVT is also reported in terms of any augmentation of the antithrombotic or hemorrhagic effects of this agent.

Objectives: The specific objective of the REDUCE trial was to evaluate the effect of low molecular weight heparin on the incidence and occurrence of restenosis in patients undergoing percutaneous transluminal coronary angioplasty (PTCA)., Background: Unfractionated heparin and its low molecular weight fragments possess antiproliferative effects and have been shown to reduce neointimal smooth muscle cell migration and proliferation in response to vascular injury in experimental studies., Methods: The REDUCE trial is an international prospective, randomized, double-blind, multicenter study. Twenty-six centers in Europe and Canada enrolled 625 patients with single-lesion coronary artery obstructions suitable for PTCA. Three hundred six patients received reviparin as a 7,000-U bolus before PTCA, followed by 10,500 U as an infusion over 24 h and then twice-daily 3,500-U subcutaneous application for 28 days. The 306 patients in the control group received a bolus of 10,000 U of unfractionated heparin followed by an infusion of 24,000 U over 24 h. These patients then underwent 28 days of subcutaneous placebo injections. The primary end points were efficacy (defined as a reduction in the incidence of major adverse events [i.e., death, myocardial infarction, need for reintervention or bypass surgery]), absolute loss of minimal lumen diameter and incidence of restenosis during the observation period of 30 weeks after PTCA., Results: Using the intention to treat analysis for all patients, 102 (33.3%) in the reviparin group and 98 (32%) in the control group have reached a primary clinical end point (relative risk [RR] 1.04, 95% confidence interval [CI] 0.83 to 1.31, p = 0.707). Likewise, no difference in late loss of minimal lumen diameter was evident for both groups. Acute events within 24 h occurred in 12 patients (3.9%) in the reviparin group and 25 (8.2%) in the control group (RR 0.49, 95% CI 0.26 to 0.92, p = 0.027) during or immediately after the initial procedure. In the control group, eight major bleeding complications occurred, and in the reviparin group, seven were observed within 35 days after PTCA., Conclusions: Reviparin use during and after coronary angioplasty did not reduce the occurrence of major clinical events or the incidence of angiographic restenosis over 30 weeks.

Reviparin is a low-molecular-weight heparin (LMWH) prepared by controlled nitrous acid digestion of porcine mucosal heparin. The trade name designation for this agent is Clivarin. This agent has been released in Germany and France for the prophylaxis of deep venous thrombosis (DVT) in surgical patients. This agent is developed utilizing optimized procedures and exhibits a uniform, narrow-molecular-weight distribution in comparison to the other commercially available LMWHs. The specific activity in the anticoagulant assays is approximated to be 32 U/mg whereas the specific activity in terms of anti-Xa units is designated 120 aXa U/mg. Reviparin is capable of producing a dose- and time-dependent antithrombotic effect in animal models of thrombosis. While the ex vivo effects are initially presented at antithrombotically active dosages, this agent has been found to produce antithrombotic effects without any detectable ex vivo actions. This agent is also known to release tissue factor pathway inhibitor (TFPI) after both intravenous (IV) and subcutaneous (SC) administration. Repeated administration of Reviparin produces progressively stronger antithrombotic effects. Similarly, the bleeding as measured by rabbit ear blood loss is also progressively increased. However, the ratio between the dosage producing these effects is quite large. The current studies are designed to provide additional data on the molecular profile using new calibration methods and additional results on the pharmacologic studies in a dose-dependent manner. In particular, the release of TFPI following IV and SC administration in a primate model is described. The effect of repeated administration mimicking the post-surgical prophylaxis of DVT is also reported in terms of any augmentation of the antithrombotic or hemorrhagic effects of these agents.

The effect of recombinant hirudin (r-hir), unfractionated heparin (UFH) and acetylsalicylic acid (ASA) on the incidence of reocclusion after thrombolysis with plasminogen activator (rt-PA) was evaluated in anaesthetized rabbits. Formation of a platelet rich thrombus was achieved by implantation of a copper coil into the iliac artery. The occluded artery was recanalized in six of ten animals by intravenous administration of rt-PA given as a bolus injection of 0.1 mg/kg followed by infusion of 0.5 mg/kg/h. Within 1 h after termination of rt-PA infusion rethrombosis was observed in 100% of recanalized vessels. The incidence of reocclusion was diminished by r-hir in a dose-dependent manner to 50% after infusion of 0.05 mg/kg/h and to 25% after 0.1 mg/kg/h. No effect on APTT was detectable in this dosage after 3 h infusion. UFH in a dosage increasing APTT two-fold (35 U/kg/h) did not reduce the reocclusion rate. 100 U/kg/h UFH increased APTT to greater than 3 min and reduced reocclusion rates to 50%. ASA showed a minor effect on the incidence of restenosis whereas the combination of 0.1 mg/kg/h r-hir plus bolus injection of 10 mg/kg ASA led to a further reduction in reocclusion rates to only 11% and an increase in reperfusion rates from 60 to 90%. Our experiments indicate that the combination of plasminogen activator with r-hir may be a useful approach for the prophylaxis of early reocclusion.

The circular dichroism spectra of a number of N-acetylneuraminic acid derivatives in aqueous solution were studied. For all compounds, the Cotton effects were found to be in the spectral range of the acetamido and carboxyl chromophores. The c.d. curves of the methy, ethyl, and allyl alpha-D-ketosides are characterized by a broad, positive band centered at lambda similar to 195 nm with a slight skew towards the higher wavelengths and weak bands between lambda 225 and 255 nm, whereas the methyl beta-D-ketoside and the corresponding methyl ester show only an intense positive band with a broad shoulder in the same spectral range. 5-Acetamido-3,5-dideoxy-D-glycero-beta-D-galacto-nonulopyranose, its methyl beta-D-ketoside, and 5-acetamido-3,5-dideoxy-D-glycero-D-galacto-nonulopyranosonamide containing only the acetamido chromophore showed one single positive Cotton effect centered at lambda similar to 192 nm. The c.d. spectrum of 5-acetamido-3,5-dideoxy-D-glycero-D-galacto-nonulopyranosonic acid confirms the beta-D configuration of the free acid in aqueous solution, whereas the shape of the c.d. curve of O-(N-acetyl-alpha-D-neuraminopyranosyl)-(2yields3)-O-beta-D-galactopyranosyl-(1 yields 4)-D-glucopyranose resembles that of the methyl, ethyl, and allyl alpha-D-ketosides 2-4.

By means of the mixed anhydride procedure the benzyl alpha-ketoside of N5-acetyl-D-neuraminic acid was linked to L-glycine, L-glutamic acid and L-phenylalanine. Hydrogenolytic cleavage of the benzyl group resulted in the corresponding free N5-acetyl-beta-D-neuraminoylpeptides. This new class of compounds is no substrate for Vibrio cholerae sialidase. The enzyme does not split the benzyl alpha-ketosides of N5-acetyl-D-neuraminoylpeptides nor is its activity inhibited by these compounds. The results strongly support the assumption that in sialidase substrates the carboxy group must be located close to the ketosidic oxygen. N-(N5-acetyl-beta-D-neuraminoyl)-L-phenylalanine was readily hydrolysed by carboxypeptidase A from bovine pancreas.

The applicability of the 5-brom-3-indolyl-alpha-ketoside of N-acetyl-D-neuraminic acid (BI-NeuAc) as substrate for the histochemical indication of neuraminidase (GOSSRAU et al. 1977) was examined in frozen sections of brain, small intestine and kidney from suckling and adult mice and respectively from a cichlid fish (Sarotherodon mosambicus) with and without formaldehyde fixation. Following biochemical investigations using tritiated gangliosides as substrate a decrease in the activity of neuraminidase took place from about 50 to 80% after tissue fixation with formaldehyde. Nevertheless significant histochemical reactions were found only in fixed tissue sections. The specificity of this reaction was shown by means of inhibitions tests using 2,3-dehydro-2-desoxy-N-acetyl-neuraminic acid according to KUMAR et al. (1981). In contrast to distinct staining of neuraminidase activity in the small intestine and kidney, only faint reactions occurred in brain sections. From this it is concluded that the application of the new synthetic substrate for quantitative staining of neuraminidase seems to be not very suitable for the CNS.

The syntheses of anomeric ethyl ketosides of 5-N-acetyl-D-neuraminic acid are described. The alpha-anomer prepared by a modified Koenigs-Knorr procedure starting from acetochloroneuraminic acid is quantitatively cleaved by Vibrio cholerae neuraminidase. Proton-catalyzed reaction of 5-N-acetyl-D-neuraminic acid with ethanol yields the beta-anomer.

This article reports on changes in lenses of diabetics, detected by means of Scheimpflug photos. Diabetics aged between 20 and 70 have been undergoing regular ophthalmogical check-ups for 26 months. Linear densitometry of negatives revealed an increase in light scatter at the anterior adjacent clear zone of disjunction (areas 1,2) and the anterior cortex (areas 3,4) in clinically clear lenses over the 26-month period. This change in light scatter is not related to the age of the patients; it is correlated to the duration of diabetes and fasting blood sugar.