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Biomedical subjects

W Jeske

Publications and source records attributed to W Jeske.

At least 19 recordsLinked to original sources
PubMed2006

Nelson's syndrome -- 46 years later: clinical experience with 37 patients.

OBJECTIVE: Pituitary tumours occurring after bilateral adrenalectomy for Cushing's disease (Nelson's syndrome) are frequently aggressive, so an early diagnosis and careful management are of prime importance. For a new insight into this entity it is necessary to analyse the factors predisposing to its development and the course of the disease, as well as the methods of diagnosis and modalities of treatment. PATIENTS AND METHODS: Thirty-seven patients with Nelson's syndrome were observed, 32 women and 5 men, aged 16 to 61 years at the time of pituitary tumour detection (at present, 27 to 82 years old). The diagnostic methods included clinical observation, imaging examinations (X-ray studies, CT, MRI), hormonal evaluation (especially ACTH and cortisol levels during replacement therapy) and ophthalmologic investigations. Neurosurgery was the main method of treatment. RESULTS: The clinical analysis indicated that young age at the time of adrenalectomy, pregnancy, insufficient replacement therapy and fulminant course of Cushing's disease were the main factors predisposing to Nelson's syndrome. MRI appeared to be the most valuable imaging method, as this detected Nelson's tumours in the microadenoma stage in 7 patients. Plasma ACTH levels varied between 32.6 pmol/l in an early phase to 2 000 pmol/l in the full-blown syndrome. Absolute temporal scotomas found in ophthalmologic examinations were an early abnormality. The best results after therapy were obtained in patients treated by neurosurgery using a transsphenoidal approach in an early stage. CONCLUSIONS: MRI, ophthalmologic examination and plasma ACTH determination were the most valuable investigations for early diagnosis of Nelson's syndrome. Early neurosurgery offered the best outcome in our group of patients.

Adolescent↗
PubMed2005

Comparative tissue factor pathway inhibitor release potential of heparins.

Tissue factor pathway inhibitor (TFPI) is released following the administration of unfractionated heparin, low-molecular-weight heparins, defibrotide and PI-88. In this study, the comparative effects of heparin, a low-molecular-weight heparin-gammaparin and a heparin-derived oligosaccharide mixture-subeparin (C3) were studied on functional and immunologic tissue factor pathway inhibitor activity levels in a non-human primate (Macaca mulatta) model. The dose-dependent effect was studied following intravenous and subcutaneous administration. Following the administration of 1 mg/kg of heparin, gammaparin, and C3, the functional levels of TFPI at 5 minutes were 2.40, 2.56, and 1.08 U/mL and the corresponding TFPI immunologic levels were 4.3-, 4.0-, and 2.1-fold, increased, respectively, over the baseline value. From these results, it can be concluded that heparin and gammaparin produced similar levels of TFPI release. Hence, gammaparin and heparin have similar TFPI release potential despite their differences in molecular weight. The influence of molecular weight, charge density, and interactions with heparin cofactor II on TFPI release are also discussed.

Animals↗
PubMed2001

Downregulation of clusterin expression in testicular germ cell tumours.

OBJECTIVES: Clusterin is implicated in many biological processes including cell adhesion, apoptosis and transformation. Clusterin expression was demonstrated during sperm maturation and is overexpressed in different malignancies including breast and prostate carcinomas and anaplastic large-cell lymphomas. METHODS: The aim of this study was to determine the expression of clusterin in a series of different germ cell tumours by immunohistochemistry. Twenty-two seminomas, 27 embryonal carcinomas, 22 mature and immature teratomas, 8 yolk sac tumours and 1 chorion carcinoma as well as 30 normal testes were analysed using a monoclonal antibody. RESULTS: In normal testes strong signals were seen in the maturing germ cells and in Leydig cells. In most tumours examined no clusterin expression was detected (84%). Only a focal weak expression was seen in some teratomas (32%), embryonal carcinomas (15%) and yolk sac tumours (25%). CONCLUSIONS: Our results suggest that clusterin is associated with normal germ cell development and that the loss of clusterin expression might play a role in the malignant transformation of germ cells.

Biomarkers↗
PubMed2001

The effect of a novel glycoprotein IIb/IIIa antagonist, SR 121566A, on platelet aggregation and activation in rhesus monkeys.

SR 121566A represents a peptidomimetic glycoprotein IIb/IIIa (GP IIb/IIIa) inhibitor 3-[N- 4-[4-(aminoiminomethyl)phenyl]-1,3-thiazol-2-yl ) -N-(1-carboxymethylpiperid-4-yl) amino] propionic acid, trihydrochloride. To investigate the intravenous and subcutaneous pharmacodynamics of this agent, a primate model ( Macaca mulatta) was used. The IC50 for adenosine diphosphate (ADP) (10 micromol/L)-induced platelet aggregation in this primate platelet system was found to be 45 +/- 6 nmol/L. Comparatively in the human platelet rich plasma system, SR 121566A demonstrated an IC50 of 39 +/- 4 nmol/L. Graded doses of SR 121566A in the range of 25-400 microg/kg were administered intravenously. Blood samples were drawn from individual groups of primates (n = 4-6) at varying periods of time up to 24 hours after administration of SR 121566A. The pharmacodynamic effects were measured by platelet aggregation using ADP (10 micromol/L) as an agonist. In addition, flow cytometric methods were used to measure thrombin receptor-activating peptide (TRAP) (6.25 micromol/L)-induced platelet activation. In the subcutaneous studies, 50, 100, 250, and 400 microg/kg of SR 121566A was administered with an identical blood-drawing schedule and analysis as with the intravenous studies. In the intravenous studies, all doses of SR 121566A produced > 80% inhibition of platelet aggregation 5 minutes after the administration of the drug. The duration of the inhibitory effect is proportional to the dose administered and the 50% recovery time ranged from 2 to 15 hours. By flow cytometry, TRAP-induced P-selectin expression was also blocked for a varying duration of time in a dose-dependent fashion. The subcutaneous studies showed > 90% inhibition of platelet aggregation, which was observed at 15 minutes after administration of both 50 and 100 microg/kg of the drug. The recovery time after the subcutaneously administered doses was found to be shorter than the intravenously administered doses. These studies demonstrate that SR 121566A is an effective platelet inhibitor with predictable pharmacokinetic and pharmacodynamic characteristics.

Adenosine Diphosphate↗
PubMed2000

Affinity purification of heparin-dependent antibodies to platelet factor 4 developed in heparin-induced thrombocytopenia: biological characteristics and effects on platelet activation.

Antibodies to heparin platelet factor 4 (H-PF4) complexes were purified from the plasma of three patients with heparin-induced thrombocytopenia (HIT) using affinity chromatography. From each plasma, the largest amount of antibodies was eluted with 2 M NaCl at pH 7.5 (peak 1) and the remainder was obtained using 0.1 M glycine/0. 5 M NaCl at pH 2.5 (peak 2). In an enzyme-linked immunosorbent assay (ELISA), we then showed that each patient had developed antibodies to PF4 displaying different characteristics. In patient 1, peak 1 IgG reacted almost exclusively with H-PF4 complexes, whereas peak 2 IgG had similar reactivity with PF4 whether or not heparin was present. Patient 2 expressed a mixture of IgA, IgM and IgG and both fractions bound to PF4 alone or to H-PF4 complexes. Finally, IgG in patient 3 only bound to H-PF4 and was unreactive with PF4 alone. Using [14C]-serotonin release assays, the antibodies developed in the three patients and exhibiting the strongest ability to activate platelets with heparin were those having the highest affinity to H-PF4. These results strongly support the hypothesis that HIT antibodies to PF4 are heterogeneous regarding their affinity and specificity for target antigens and this may greatly influence their ability to activate platelets and their pathogenicity.

Anticoagulants↗
PubMed2000

Isoamyl nitrite depolymerized heparin as a universal calibrator for heparins and low molecular weight heparins.

Because the subcutaneous absorption of heparin depends on its molecular weight, high performance size exclusion chromatography methods, among others, have been developed for its determination. Because heparin consists of polymer chains of varying lengths, a large number of calibrators, 19 in our work, are required for these molecular weight analyses. Because the preparation of that many calibrants is both time-consuming and expensive, other methods requiring fewer calibrants are being sought. In pursuit of these aims, a heparinase-degraded heparin has been accepted as the first international reference preparation low molecular weight heparin for molecular weight calibration. We have previously proposed another calibrant, the Heparin Mass Calibrator. In this article, we introduce another calibrant, called the Heparin Molecular Mass Calibrant. It offers the advantage of a much wider availability because it is a commercial product. In addition to having a superior refractive index chromatography run profile, when used in combination with two Narrow Range Calibrators with molecular weights of 34.4 and 18.4 kDa, this new calibrant covers both the higher and the lower molecular weight ranges. Besides, ultraviolet detection is not needed for molecular weight calculations. Therefore, it is proposed that its feasibility as a universal reference calibrator for both heparins and low molecular weight heparins be considered.

Amyl Nitrite↗
PubMed2000

[MEN 2A syndrome: report of a family].

A typical three generation-family with MEN 2A (Multiple Endocrine Neoplasia, Type 2A) is described. Two brothers and their uncle were affected with medullary thyroid carcinoma (MTC) and pheochromocytoma. The diagnosis of MTC was based on calcitonin determinations after pentagastrin stimulation. Pheochromocytoma was clinically silent in two cases. A family screening with pentagastrin test led to the diagnosis of C cell hyperplasia in a 8-year boy, who was then successfully operated on. The authors discuss the value of pentagastrin test and genetic testing in the early diagnosis of MTC associated with MEN 2A syndrome.

Adult↗
PubMed1999

Structural features and anticoagulant activities of a novel natural low molecular weight heparin from the shrimp Penaeus brasiliensis.

A natural low molecular weight heparin (8.5 kDa), with an anticoagulant activity of 95 IU/mg by the USP assay, was isolated from the shrimp Penaeus brasiliensis. The crustacean heparin was susceptible to both heparinase and heparitinase II from Flavobacterium heparinum forming tri- and di-sulfated disaccharides as the mammalian heparins. (13)C and (1)H NMR spectroscopy revealed that the shrimp heparin was enriched in both glucuronic and non-sulfated iduronic acid residues. The in vitro anticlotting activities in different steps of the coagulation cascade have shown that its anticoagulant action is mainly exerted through the inhibition of factor Xa and heparin cofactor II-mediated inhibition of thrombin. The shrimp heparin has also a potent in vivo antithrombotic activity comparable to the mammalian low molecular weight heparins.

Animals↗
PubMed1999

Inactivation of factor Xa by the synthetic inhibitor DX-9065a causes strong anticoagulant and antiplatelet actions in human blood.

In an in vitro study, anticoagulant and antiplatelet effects of the synthetic, direct factor Xa inhibitor DX-9065a, (+)-2S-2-[4-[[(3S)-1-acetimidoyl-3-pyrrolidinyl]oxy]phenyl]-3-[7-a midino-2-naphthyl]propanoic acid hydrochloride pentahydrate, which shows a high affinity and selectivity towards the enzyme, were investigated. Anticoagulant actions of DX-9065a were studied in human plasma using global clotting assays [prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT) and Heptest]. The effect on thrombin generation was measured in whole blood by determining the plasma concentration of prothrombin fragment F1.2. The influence on agonist-induced platelet activation in whole blood was studied using flow cytometric analysis. DX-9065a caused a concentration-dependent prolongation of clotting times in the PT and APTT assay, whereas Heptest was less affected and TT was not influenced. Furthermore, DX-9065a strongly inhibited the generation of thrombin without and after coagulation activation. The factor Xa inhibitor did not affect platelet activation mediated by either thrombin receptor activating peptide, arachidonic acid or y-thrombin, but prevented tissue factor- and factor Xa-induced activation of platelets in a concentration-dependent manner. Inactivation of factor Xa by a highly effective and selective inhibitor, and the resulting inhibition of thrombin generation leads to strong anticoagulant and antiplatelet actions. The interference with the coagulation system at the early level of factor Xa is expected to be an effective approach for a successful anticoagulant/antithrombotic therapy.

Anticoagulants↗
PubMed1999

Pharmacologic profile of certoparin.

The low molecular weight heparins (LMWHs) are now not only used for the prophylaxis and treatment of deep vein thrombosis (DVT), but also for the management of acute coronary syndromes. Beside these approved usages, the LMWHs have been developed for indications such as thrombotic and ischaemic stroke, cancer-associated thrombotic and vascular disorders, Alzheimer's disease and a variety of inflammatory disorders. In the United States, there are three approved LMWHs (enoxaparin, dalteparin and ardeparin). In Canada, reviparin and tinzaparin are also approved. The European Union has taken the lead; eight LMWHs are approved for various indications. Certoparin represents one of the earlier LMWHs used for DVT prophylaxis and treatment, with additional indications currently under development. Certoparin represents an isoamyl nitrite depolymerised LMWH with comparable structural characteristics to other nitrous acid depolymerised products such as nadroparin and reviparin. While comparable in structure to dalteparin, this agent differs in function due to a secondary purification process that is employed in the manufacture of dalteparin. The preclinical pharmacology of this drug has been extensively investigated. Although indication specific dosing and the optimisation of use in, for example, acute coronary syndromes and thrombotic stroke, may be require, certoparin represents a typical LMWH with comparable performance characteristics to some other agents. This chapter describes some of the preclinical and clinical pharmacologic characteristics of this drug. This information will be useful in designing clinical trials for newer indications of this drug.

Journal Article↗
PubMed1999

Pharmacology of argatroban.

Argatroban, a synthetic peptidomimetic antithrombin agent, is the first clinical anticoagulant solely to target thrombin. For some time, this drug has been used in Japan for the management of thromboembolic disorders. Recently, it has been approved in Japan for use in thrombotic and ischaemic stroke. Despite a large number of preclinical studies on the pharmacology of this agent, clinical trials in Europe and North America were only initiated in 1996. Argatroban produces anticoagulant effects comparable to therapeutic heparinisation at concentrations of approximately 1 microg/ml. At concentrations of 5-10 microg/ml, this agent produces adequate anticoagulation for inteventional cardiovascular procedures and prolongs the activated clotting time (ACT) to 400-600 s. The predictable anticoagulant effect of this agent is relatively short lasting, and may not warrant pharmacologic neutralisation in the majority of patients. However, patients with hepatic dysfunction may need some means of neutralisation. Unlike heparin, this drug produces its anticoagulant effects by direct inhibition of thrombin and thrombin-mediated processes. This agent is not influenced by endogenous factors such as platelet factor 4 and other proteins which bind heparin. Argatroban's use does not lead to the formation of antiplatelet antibodies. Thus, this drug is useful in the management of heparin induced thrombocytopenic (HIT) patients. Although argatroban was initially developed for the management of deep vein thrombosis (DVT), based on its pharmacologic properties, it can be developed for safer anticoagulation in such indications as acute coronary syndromes, as an adjunct to thrombolytics, thrombotic and ischaemic stroke and inflammatory diseases resulting in thrombotic complications.

Journal Article↗
PubMed1999

In vitro studies on the biochemistry and pharmacology of low molecular weight heparins.

Low molecular weight heparins (LMWHs) are obtained from unfractionated heparin by diverse chemical and enzymatic processes and findings with one LMWH cannot be extrapolated to another. Functional assays performed in vitro, evaluating antiprotease activity mediated via antithrombin III, heparin cofactor II interactions, antithrombin III binding, and plasma protein binding, showed wide variations between LMWHs, indicating that compositional differences among the LMWHs have a major impact on function. Evaluation in vitro showed varying potency in United States Pharmacopeia (USP) and anti-Xa assays. LMWHs tested at anti-Xa-adjusted concentrations exhibited varying potencies with anti-IIa, Heptest, and activated partial thromboplastin time (APTT) assays. Evaluation of these assays showed differences between LMWHs and a link with molecular weight. Each LMWH also varied in the in vitro neutralization by platelet factor 4, thrombin, and heparinase. LMWHs also varied in platelet interactions as assessed by whole blood clotting, thromboelastography and P-selectin expression, and in tissue factor pathway inhibitor release in cell culture. It was concluded that compositional variations in LMWHs give each product a unique biochemical profile. This profile, plus varying endogenous interactions and pharmacokinetic profiles may give rise to the clinical differences observed with LMWHs in specific indications.

Animals↗
PubMed1998

Low-molecular-weight heparins: pharmacologic profile and product differentiation.

The interchangeability of low-molecular-weight heparins (LMWHs) has been the subject of discussion since these products were first introduced for the prophylaxis of deep vein thrombosis. Experimental evidence now exists to show that LMWHs differ from each other in a number of characteristics. Products have been differentiated on the basis of molecular weight and biologic properties, but only limited information derived from the clinical setting is available. Potency has been described on the basis of anti-Factor Xa activity, but at equivalent anti-Xa activities, the anti-Factor IIa activity of different products shows marked variations. At the relatively small doses used for the management of postsurgical deep vein thrombosis, the effect of these interproduct differences may be relatively minor, but as LMWHs are developed for therapeutic use at much higher doses, such differences may become clinically important. Variations in safety and efficacy reported in clinical trials of LMWHs may reflect the known differences in their molecular composition and pharmacologic properties.

Animals↗
PubMed1998

Low molecular weight heparins: are they different?

In addition to their use in postsurgical and medical prophylaxis of deep vein thrombosis (DVT), low molecular weight heparins (LMWHs) are being developed for cardiovascular and cerebrovascular indications. Because of manufacturing differences, each LMWH exhibits distinct pharmacological and biochemical profiles that may influence clinical performance. The specific activity of these agents in anticoagulant assays ranges from 35 to 45 anti-IIa U/mg or 80 to 120 anti-Xa U/mg. LMWHs are capable of producing product-specific dose- and time-dependent antithrombotic effects in animal models of thrombosis. While the ex vivo effects are initially present at antithrombotic doses, these agents have been found to produce sustained antithrombotic effects without any detectable ex vivo anticoagulant actions. In experimental animal models and in various clinical trials, these agents have also been found to release tissue factor pathway inhibitor (TFPI) after both intravenous and subcutaneous administration. Repeated administration of LMWHs produces progressively stronger antithrombotic effects. However, the hemorrhagic responses vary and are largely product dependent. The product-dependent release of TFPI following intravenous and subcutaneous administration in a primate model also demonstrates the relevance of this inhibitor to the actions of LMWHs. The effect of repeated administration of LMWH mimicking the postsurgical prophylaxis of DVT exhibited product-based augmentation of the antithrombotic or hemorrhagic effects.

Animals↗
PubMed1997

In vitro studies on the effect of activated protein C on platelet activation and thrombin generation.

The effect of activated protein C (APC) on agonist-induced platelet activation and on thrombin generation after intrinsic (IA) and extrinsic (EA) activation of the coagulation system was studied by flow cytometry and by measuring levels of prothrombin fragment F1+2. In platelet activation studies blood drawn from healthy volunteers was anticoagulated with 10 micrograms/ml APC and incubated at 37 degrees C either with saline, recombinant tissue factor (r-TF), arachidonic acid (AA), ADP or collagen. At definite times aliquots were taken and processed for flow studies. Platelet activation was measured using fluorescent monoclonal antibodies to platelet surface receptors GPIIIa (CD-61) and P-selectin (CD-62). Flow cytometric analysis showed platelet activation after all agonists used. APC did not influence AA-, ADP- and collagen-induced platelet activation but completely inhibited activation of platelets induced by r-TF. The effect of APC on r-TF-mediated platelet activation was concentration-dependent in the range of 0.5 to 20 micrograms/ml showing an increase in CD-62 expression at lower concentrations. In citrated and APC-anticoagulated blood the generation of thrombin was studied after IA and EA. At 10 and 20 micrograms/ml APC effectively prevented blood clotting which rapidly occurred especially after EA. The amount of thrombin generated via the extrinsic pathway was reduced by APC whereas after IA F1+2 levels measured in the presence of APC were still strongly increased. These results indicate that small amounts of thrombin generated by r-TF are sufficient to activate platelets as well as blood coagulation. APC exerts strong concentration-dependent anticoagulant actions and effectively prevents activation of platelets.

Cells, Cultured↗