Biomedical subjects

G Nowak

Publications and source records attributed to G Nowak.

At least 19 recordsLinked to original sources

PubMed2006

Prospective studies in patients with intraventricular haemorrhage without the capacity to give consent in Germany--a legal dilemma.

OBJECTIVE: The prognosis of intracranial haemorrhage with ventricular participation is poor. The acute onset of hydrocephalus has to be treated with an external ventricular drainage. However, intraventricular blood clots often obstruct the drainage catheter; the reinsertion is usually associated with an increased risk of complications. Therefore, intraventricular thrombolysis using recombinant tissue plasminogen activator (rt-PA), urokinase or streptokinase has been performed in several cases. In Germany, rt-PA does not have approval for intraventricular applications, and the risks and benefits of this treatment are as yet unclear. Several authors recommend its use only in the frame of prospective studies, meaning that intraventricular administration of thrombolytic agents within an individual therapy trial could be viewed as medical malpractice. METHODS: We designed a national prospective randomised and controlled study in patients with intraventricular haemorrhage to investigate the risks and effects of intraventricular rt-PA treatment. The local ethics committee and lawyers did not accept the study protocol due to a non-acceptable risk of complications. In two further conferences, the risk of undertreatment in the control group was a major reason not to accept the protocol. We discuss the conflicts of law in related studies. CONCLUSIONS: There is a need for a solution to the legal conflicts of medical malpractice, unclear risk-benefit ratio and unfeasibility due to risk of complications or undertreatment in studies with patients without the capacity to give informed consent.

Antifibrinolytic Agents↗

PubMed2006

Antidepressant-like activity of CGP 36742 and CGP 51176, selective GABAB receptor antagonists, in rodents.

BACKGROUND AND PURPOSE: A crucial role for the GABAB receptor in depression was proposed several years ago, but there are limited data to support this proposition. Therefore we decided to investigate the antidepressant-like activity of the selective GABAB receptor antagonists CGP 36742 and CGP 51176, and a selective agonist CGP 44532 in models of depression in rats and mice. EXPERIMENTAL APPROACH: Effects of CGP 36742 and CGP 51176 as well as the agonist CGP 44532 were assessed in the forced swim test in mice. Both antagonists were also investigated in an olfactory bulbectomy (OB) model of depression in rats, while CGP 51176 was also investigated in the chronic mild stress (CMS) rat model of depression. The density of GABAB receptors in the mouse hippocampus after chronic administration of CGP 51176 was also investigated. KEY RESULTS: The GABAB receptor antagonists CGP 36742 and CGP 51176 exhibited antidepressant-like activity in the forced swim test in mice. The GABAB receptor agonist CGP 44532 was not effective in this test, however, it counteracted the antidepressant-like effects of CGP 51176. The antagonists CGP 36742 and CGP 51176 were effective in an OB model of depression in rats. CGP 51176 was also effective in the CMS rat model of depression. Administration of CGP 51176 increased the density of GABAB receptors in the mouse hippocampus. CONCLUSIONS AND IMPLICATIONS: These data suggest that selective GABAB receptor antagonists may be useful in treatment of depression, and support an important role for GABA-ergic transmission in this disorder.

Animals↗

PubMed2006

The use of PEG-Hirudin in chronic hemodialysis monitored by the Ecarin Clotting Time: influence on clotting of the extracorporeal system and hemostatic parameters.

AIM: The aim of our study was to investigate the use of polyethylene glycol (PEG)-Hirudin (PEG-H) as an anticoagulant in hemodialysis including drug monitoring with the Ecarin Clotting Time (ECT) in whole blood and to compare this regimen with standard anticoagulant unfractionated heparin (UFH) for influence on hemostatic parameters and clot frequency of the extracorporeal system. PATIENTS AND METHODS: The application of PEG-H as an anticoagulant in patients on chronic HD was studied in 20 patients (12 males, 8 females) from a single center in an exploratory, open-label, controlled, single-blind, dose-finding study. The patients were divided in 2 groups with 10 patients each (Group I and II); both received 3 dialyses with UFH, thereafter Group I received 5 dialyses with PEG-H and Group II 10 dialyses with PEG-H. Starting dose of PEG-H in the first dialysis was a bolus of 0.08 mg/kg bwt, the mean dose of the following HD was 0.041 mg/kg bwt (range 0.026 0.065 mg/kg bwt). PEG-H was applied as an intravenous bolus-dose followed by a 0.9% saline as a placebo-infusion. HD was performed regularly 3 times a week. All dialysis treatments were performed exclusively with a hollow fiber dialyzer type. Fibrinogen, antithrombin III, prothrombin fragments, thrombin-antithrombin and soluble fibrin were measured with commercial tests. ECT was determined in a mechanical coagulometer. A semiquantitative score was given for the presence of clots in the extracorporeal system after each dialysis. RESULTS: PEG-H was effectively used as an anticoagulant in 150 chronic dialysis treatments using ECT as a simple monitoring method. The optimal whole blood concentration for PEG-H is 600-1000 ng/ml. Clotting in the whole extracorporeal system was decreased by 45% (p = 0.059) with PEG-H anticoagulated HD in comparison to UFH. Fibrinogen, prothrombin fragments (F1+2-fragments) and thrombin-antithrombin-complex showed no significant change in comparison with UFH, antithrombin III (AT III) increased to normal concentrations. Highly sensitive coagulation markers such as a soluble fibrin showed a significant decrease (p < 0.001) before and after HD with PEG-H compared with UFH. CONCLUSION: PEG-H can be used effectively as an alternative anticoagulant in patients on chronic HD using ECT as a simple drug monitoring method. The lower frequency of clots in the extracorporeal system, the stronger and more efficient inhibition of coagulation during HD as indicated by soluble fibrin, may have a positive influence on the disturbed blood coagulation of these patients.

Adult↗

PubMed2005

[Familial cavernous malformations of the central nervous system. A clinical and genetic study of 15 German families].

In 1928, Hugo Friedrich Kufs reported on a family with cerebral, retinal, and cutaneous cavernous malformations. Since then, more than 300 families with inherited cavernous malformations have been reported. Genetic studies showed three loci, on chromosomes 7q21-q22 (with the gene CCM1), 7p15-p13 (CCM2), and 3q25.2-q27 (CCM3). The gene product of CCM1 is Krit 1 (Krev interaction trapped 1), a protein interacting with angiogenesis by various mechanisms. Recently, CCM2 has also been identified; its product is a protein which might have a function similar to that of Krit 1. However, the CCM3 gene has still not been found. In this study, we present clinical and genetic findings on 15 German families.

Adult↗

PubMed2005

Cerebellar haemorrhage and tension pneumocephalus after resection of a Pancoast tumour.

We present an unusual case of cerebellar haemorrhage followed by tension pneumocephalus several days after thoracotomy for resection of a Pancoast tumour. The postoperative course of the 32-year-old patient was complicated by a cerebellar haemorrhage and hydrocephalus caused by compression of the fourth ventricle. Immediate surgical evacuation of the haemorrhage and placement of an external ventricular drain was performed. Respirator ventilation maintaining a continuous positive airway pressure was required. Following weaning and extubation the patient rapidly deteriorated and became comatose. A cranial CT scan revealed a dilated ventricular system filled with air, and air in the subarachnoid space. Recovery of consciousness was observed after aspiration of intracranial air through the ventricular drainage. Recurrent deterioration of consciousness after repeated air aspiration indicated rapid refilling of the ventricles with air. The patient underwent emergency surgical re-exploration of the thoracic resection cavity: dural lacerations of the cervico-thoracic nerve roots C8 and Th1 were identified. Subarachnoid-pleural fistula, cerebellar haemorrhage and tension pneumocephalus after discontinuation of continuous positive airway pressure respiration are unusual complications of thoracic surgery. We discuss the putative pathomechanisms and present a brief review of the literature.

Adult↗

PubMed2005

Identification of expandable human hepatic progenitors which differentiate into mature hepatic cells in vivo.

BACKGROUND: Liver diseases include a wide spectrum of both acute and chronic conditions which are associated with significant morbidity and mortality worldwide. Hepatocyte transplantation has therapeutic potential in the treatment of liver diseases, but its clinical use is hampered by the lack of donor tissue. Generation of hepatocytes in vitro from adult or fetal liver cell progenitors or, alternatively, identification of a progenitor population which in vivo can generate mature liver cells could solve this problem. METHODS: CD117+/CD34+/Lin- human fetal liver cells were isolated by magnetic cell sorting and expanded in culture. Both freshly isolated and in vitro expanded cells in various passages were studied for their ability to be functional in hepatic parenchyma following d-galactosamine (GalN) induced injury in nude C57 black mice. RESULTS: Freshly isolated and in vitro expanded CD117+/CD34+/Lin- cells, when transplanted intrasplenically into GalN treated mice, morphologically and functionally differentiated into hepatocytes and cholangiocytes. Human specific albumin, alpha fetoprotein, cytokeratin 19, and antitrypsin mRNA were expressed in mouse liver. In addition, the human progenitor cells expressed glucose-6-phosphatase, glycogen, albumin, gamma glutamyl transpeptidase, and dipeptidyl peptidase IV after transplantation. Expanded cells in various passages maintained their capacity to differentiate into functional liver cells. CONCLUSIONS: Fetal liver CD117+/CD34+/Lin- progenitors and their progeny proliferated in vitro and also functionally differentiated into mature hepatic cells in an acute liver injury model. Successful in vitro expansion of liver progenitor cells provides a basis for developing cell therapy strategies, metabolic and toxicity testing systems, and may serve as a vehicle for gene therapy.

Animals↗

PubMed2005

Chromogenic substrates as fundamental tool to design new thrombin inhibitors. Determination of inhibition equilibrium constants.

The structure-activity relationship of dipetalogastin II, the strongest thrombin inhibitor isolated and cloned from the bug Dipetalogaster maximus, was examined by introducing gradual changes into the molecule by means of molecular biological methods. The effect upon its inhibition equilibrium constant was determined after each change by a chromogenic assay. This structural information was fundamental to design new dipetalogastin II-derived inhibitors. Our results suggested that the acidic sequence DEHDHDFEDT corresponding to amino acid residues 49 to 58 of dipetalogastin II reacts with the anion binding exosite (ABE) 1 of thrombin. Based on this finding, we constructed a chimeric molecule consisting of the active site blocking segment of dipetalogastin II (amino acid residues 1 to 48) and the ABE 1 blocking segment of hirudin. This construct showed better thrombin inhibitory activity than both separated segments only after the introduction of a glycine linker between both blocking segments. We thus obtained a thrombin inhibitor called dipetarudin with an inhibition equilibrium constant comparable to that of dipetalogastin II and a molecular mass below that of dipetalogastin.

Antithrombins↗

PubMed2005

[Ecarin chromogenic assay: an innovative test for quantitative determination of direct thrombin inhibitors in plasma].

The ecarin chromogenic assay (ECA) was developed for quantitative determination of direct thrombin inhibitors. As a further development of the ecarin clotting time (ECT), the ECA is based on the same principle, the activation of prothrombin by ecarin a snake venom from Echis carinatus. In the ECA the prothrombin activation products meizothrombin and meizothrombin-desF1 cleave a chromogenic substrate, whereas in the clotting assay ECT plasma fibrinogen is converted to fibrin. The activity of meizothrombin/meizothrombin-desF1 is inhibited in a concentration-dependent fashion by direct thrombin inhibitors. The ECA can be used as ECA-H for quantitative determination of hirudin and as ECA-T for determination of synthetic thrombin inhibitors. As shown for hirudin, argatroban and melagatran, the ECA turned out as a very precise and sensitive method, which combines the advantages of ECT with those of chromogenic assays. In ECA very low interindividual variations were found compared to aPTT and even ECT. The ECA is independent of the variations of the coagulation variables prothrombin and fibrinogen.

Animals↗

PubMed2004

Three recombinant serine proteinase inhibitors expressed from the coding region of the thrombin inhibitor dipetalogastin.

Dipetalogastin is a potent thrombin inhibitor from Dipetalogaster maximus. The cDNA of dipetalogastin codes for a large protein which consists of six Kazal-type domains. There are three tandem, homologous regions each including two domains. Three biologically active recombinant proteins rDI, rDII and rDIII each corresponding to one region of the dipetalogastin cDNA were expressed, purified and investigated with regard to their biological activities. rDI and rDII with molecular masses of 12,660 and 12,911 Da, respectively, proved to be potent thrombin inhibitors. The investigation of their influences on amidolytic activities of different serine proteases showed no inhibition of factor Xa (FXa) and alpha-chymotrypsin. At a large molar excess of rDI and rDII over the enzymes only low effects on the activities of trypsin and plasmin were observed. rDIII differs much from the both others. An inhibition of thrombin was found only at a molar excess of rDIII over the enzyme. Furthermore, an inhibition of trypsin and low effects on plasmin were detected at a molar excess of inhibitor over these enzymes. These results indicate that rDIII is active against thrombin, trypsin and plasmin, and finally possesses no specificity for only one serine proteinase.

Amino Acid Sequence↗

PubMed2004

Group III mGlu receptor agonists produce anxiolytic- and antidepressant-like effects after central administration in rats.

It was well established that compounds which decrease glutamatergic transmission via blockade of NMDA or group I mGlu receptors produce anxiolytic- and antidepressant-like action in animal tests and models. Since group III metabotropic glutamate receptor (mGluR) agonists are known to reduce glutamatergic neurotransmission by the inhibition of glutamate release, we decided to investigate potential anxiolytic- and/or antidepressant-like effects of group III mGluR agonists, after central administration in rats. It was found that group III mGluR agonists, (1S,3R,4S)-1-aminocyclo-pentane-1,3,4-tricarboxylic acid (ACPT-I) and 2-amino-4-(3-hydroxy-5-methylisoxazol-4-yl)butyric acid (HomoAMPA), given intrahippocampally, produced a dose-dependent anxiolytic-like effect in the conflict drinking test. The effects of ACPT-I and HomoAMPA were reversed by (RS)-alpha-cyclopropyl-4-phosphonophenyl glycine (CPPG), group III mGluR antagonist. Moreover, a dose-dependent antidepressant-like action of group III mGluR agonists, ACPT-I and (RS)-4-phosphonophenylglycine (RS-PPG), but not HomoAMPA, was found in behavioral despair test, after intracerebroventricular injections, and the effect of ACPT-I was reversed by CPPG. The results obtained indicate that group III mGluR agonists produce anxiolytic- as well as antidepressant-like effects in behavioral tests, after central administration in rats. The reduction of glutamate release by group III mGluR activation may be a possible mechanism underlying anxiolytic- and antidepressant-like properties of the tested compounds. In conclusion, the results of our studies indicate that group III mGlu receptor agonists may play a role in the therapy of both anxiety and depression.

Animals↗

PubMed2004

[Monitoring of platelet function inhibitors: requirements for analytic strategies].

In this survey, the requirements for platelet function analysis are reviewed from a haemostaseologist's point of view. Problems and difficulties in platelet function diagnostics, i. e. in the methods and procedures used for measurement are described. Although drugs that interfere with certain parts of platelet function become more and more precise, we did not succeed in treating the patient with the optimal drug and in monitoring its efficacy accurately. A new quality of drug therapy is to be reached in order to immediately recognise idio-syncrasies, toxic reactions or drug induced side effects. For this, in time POCT methods should be used by medical staff. Furthermore, the methodical range of haemostaseologic laboratories should guarantee a high quality in acute and long-term drug monitoring.

Blood Platelets↗

PubMed2004

[Platelet Adhesion Assay (PADA), a new quantitative test for assessment of platelet function and therapeutic drug monitoring of GPIIb/IIIa and ADP receptor antagonists].

Platelet ADhesion Assay (PADA) is a POCT capable method for quantitative determination of platelet adhesiveness. Using special polymer particles and test conditions adjusted to the physiologic conditions, the current functional state of blood platelets is determined directly from a whole blood sample. Within a short time, using little technical equipment and small sample volume, a therapeutic drug monitoring of GP IIb/IIIa and ADP receptor antagonists is possible, too. Whereas in healthy volunteers dose/effect curves of GP IIb/IIIa antagonists vary only slightly, in thrombopilic patients there are big variations. Differences in efficacy up to drug resistance may occur also in use of the ADP receptor antagonist clopidogrel. A therapeutic drug monitoring of GP IIb/IIIa- and ADP receptor antagonist therapy is essential and becomes feasible using PADA, also as long-term drug monitoring of ADP receptor antagonists and detection of drug resistance. Additionally, an individual ex vivo dose estimation for GP IIb/IIIa antagonists is possible. PADA allows diagnostics of pathological platelet function in thrombophilic patients as well as long-term therapeutic drug monitoring due to its simple handling.

Blood Specimen Collection↗

PubMed2004

Outcome and prognostic factors of hemicraniectomy for space occupying cerebral infarction.

OBJECTIVE: To determine long term functional outcome and length of survival of patients undergoing decompressive craniectomy for space occupying infarction of the middle cerebral artery (MCA), and to identify risk factors associated with death and unfavourable outcomes METHODS: Databases of patients undergoing decompressive craniectomy for space occupying MCA infarction compiled at eight neurosurgical departments (1996-2001) were merged, and 188 patients were evaluated. Mortality was calculated by the Kaplan-Meier method. Clinical outcome was rated using the Glasgow outcome scale (GOS). The prognostic impact of patient related covariates on length of survival and the GOS was analysed multivariately. RESULTS: The unadjusted 3, 6, and 12 month mortality rates were 7.9%, 37.6%, and 43.8%, respectively (median follow up, 26 weeks). In the "best" multivariate model, age >50 years (p<0.02) and the involvement of two or more additional vascular territories (p<0.01) had an unfavourable impact on length of survival. The adjusted six month mortality was as low as 20.0% (no risk factor) and as high as 59.7% (two risk factors). A GOS score of 50 years (p<0.0003): 34.9% of the patients 3, as compared with 12.0% of the elderly subpopulation. The side of the infarct did not have prognostic relevance. CONCLUSIONS: Results of surgical treatment in patients <50 years of age undergoing decompressive craniectomy are encouraging. The effectiveness of decompressive craniectomy for patients >50 years remains questionable and should be analysed in the framework of a prospective randomised study.

Adolescent↗

PubMed2004

Synthesis of new hexahydro- and octahydropyrido[1,2-c]pyrimidine derivatives with an arylpiperazine moiety as ligands for 5-HT(1A) and 5-HT(2A) receptors, Part 2.

The synthesis of new of 4-aryl-hexahydro- (11-16) and (R,R)(S,S)4-aryl-octahydropyrido[1,2-c]pyrimidine (23-27) derivatives bearing a aryl- or heteroarylpiperazinyl moiety in position 2 is described. The derivatives of 4-aryl-hexahydro- (1-5) and (R,R)(S,S)4-aryl-octahydropyrido[1,2-c]pyrimidin-1,3-dion (17-19) served as starting compounds for further synteses. The N-alkylation of the imide moiety in compounds 1-5 and 17-19 by 1,4-dibromobutane gave the respective monbromobutyl derivatives 6-10 and 20-22. The final derivatives 11-16 and 23-27 have been produced by condensation of the obtained bromoderivatives with selected 1-aryl and 1-heteroarylpiperazines. Compounds 11-16 and 23-27 were tested for their affinity towards 5-HT(1A), 5-HT(2A) and alpha1 receptors, using a radioligand binding assay.

Animals↗

PubMed2003

Cloning, purification and biochemical characterization of dipetarudin, a new chimeric thrombin inhibitor.

The development of thrombin inhibitors could provide invaluable progress for antithrombotic therapy. In this paper, we report the cloning, purification and biochemical characterization of dipetarudin, a chimeric thrombin inhibitor composed of the N-terminal head structure of dipetalogastin II, the strongest inhibitor from the assassin bug Dipetalogaster maximus, and the exosite 1 blocking segment of hirudin, connected through a five glycine linker. The cloning of dipetarudin was performed by a simple method which had not been used previously to clone chimeras. Biochemical characterization of dipetarudin revealed that it is a slow, tight-binding inhibitor with a molecular mass (M(r)=7560) and a thrombin inhibitory activity (K(i)=446 fM) comparable to r-hirudin.

Antithrombins↗

PubMed2003

Influence of displayed image size on radiographic detection of approximal caries.

OBJECTIVES: To evaluate the validity of approximal caries detection on digital bitewing radiographs displayed at different image sizes on either a cathode ray tube (CRT) monitor or a thin film transistor (TFT) monitor. METHODS: Five observers assessed digital radiographs of a charge-coupled device (CCD)-based sensor system (Sidexis) of 160 unrestored premolars and molars for approximal caries using a six category caries rating scale. Images were displayed at ratios of 1:1, 1:2 and 1:7 on a CRT monitor (Nokia 446 XS) and a TFT display (Panasonic LC 50S). Histological assessments of serial sections were used as the validation standard. Diagnostic accuracy was expressed as area under the receiver operating characteristic (ROC) curve (AUC) and was calculated at two levels of caries penetration: presence of caries (I) and presence of a lesion in the dentine (II). The influence of the factors "monitor type", "image size" and "validation threshold" were analysed with repeated measures analysis of variance. RESULTS: The ROC curve areas for approximal caries detection at both histological penetration levels were not influenced by the type of monitor display, whereas image size had a significant impact (P<0.01). AUCs for image size 1:7 (I, 0.62; II, 0.65) were smaller compared with ratios of 1:1 and 1:2 (P<0.01). No differences were observed between image size ratios 1:1 (I, 0.69; II, 0.74) and 1:2 (I, 0.68; II, 0.73). CONCLUSIONS: In this study, the type of monitor did not influence approximal caries detection on digital radiographs. Image sizes with a display ratio of 1:1 and 1:2 resulted in better diagnostic validity than those with a ratio of 1:7.

Analysis of Variance↗

PubMed2003

Remifentanil-propofol versus sufentanil-propofol anaesthesia for supratentorial craniotomy: a randomized trial.

BACKGROUND AND OBJECTIVE: Remifentanil has unique pharmacokinetics that might allow faster recovery after neurosurgery. We investigated the effects of a propofol/sufentanil versus a remifentanil/propofol regimen on the primary end-point tracheal extubation time. METHODS: In the Neurosurgery Department of a University Hospital, 36 patients awaiting craniotomy for supratentorial tumour resection were randomly assigned to one of two study groups. In the sufentanil/propofol group, anaesthesia was induced with 0.5 microg kg(-1) sufentanil and 1-2 mg kg(-1) propofol. Propofol infusion and boluses of sufentanil were administered for maintenance. In the remifentanil/propofol group, anaesthesia was started with an infusion of remifentanil (0.2-0.35 microg kg(-1) min(-1)) and a bolus of propofol (1.5-2 mg kg(-1)). Patients received a propofol infusion and a remifentanil infusion for maintenance of anaesthesia. Recovery times were taken from cessation of the propofol infusion. In addition, data about self-reported nausea and vomiting, pain and analgesic requirements were collected. RESULTS: Patients in the remifentanil/propofol group were extubated earlier (mean times 6.4 (+/- SD 4.7) versus 14.3 (+/- 9.2) min; P = 0.003). The two groups were similar with respect to postoperative nausea and vomiting, and patient-reported pain scores. Fifty per cent of the remifentanil/propofol patients and 88% of the sufentanil/propofol patients required no analgesics within 1 h after operation (P = 0.03). CONCLUSIONS: The remifentanil/propofol regimen provided quicker recovery. The two regimens were similar in terms of postoperative nausea and vomiting and patient-reported pain scores, but patients in the remifentanil/ propofol group required more analgesics within 1 h postoperatively.

Aged↗

PubMed2003

Evaluation of some aroxyethylamine derivatives for hypotensive properties and their affinities for adrenergic receptors.

A series of aroxyethylamines (1-10) was synthesized and evaluated for hypotensive activity in rats after intravenous and oral administration. The 4 compounds (4, 7, 8 and 10) containing a (2-methoxy)phenylpiperazine moiety displayed hypotensive activity and their affinities for alpha1-, alpha2- and beta1-adrenoreceptors were determined by radioligand binding assays. Compounds 4, 7, 8 and 10 were also tested for their effect on the pressor responses to epinephrine, norepinephrine, methoxamine, tyramine and DMPP. The results suggest that the hypotensive effect of these compounds is related to their alpha- and beta-adrenolytic properties.

Administration, Oral↗