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Biomedical subjects

R Zimmermann

Publications and source records attributed to R Zimmermann.

At least 397 records · Page 22Linked to original sources
PubMed1989

Chemical synthesis and enzymic processing of precursor forms of cecropins A and B.

Radiolabeled preprocecropin B, with an alpha-amidated COOH terminus, and preprocecropin A, extended at the COOH terminus by a glycine residue, were synthesized by solid-phase methods. The respective syntheses were interrupted at intervals to allow the preparation of the predicted procecropins A and B as well as three other truncated derivatives of the cecropin A precursors. All the synthetic peptides were purified to near homogeneity by reverse-phase liquid chromatography and their purity was established by analytical high performance liquid chromatography, gel electrophoresis, and amino acid analysis. A dipeptidyl aminopeptidase was purified about 350 times from the hemolymph of cecropia pupae and characterized by its affinity for different substrates and inhibitors. The synthetic prepro peptides were tested for processing by an extract of dog pancreas microsomes and purified leader peptidase from Escherichia coli, with and without partly purified dipeptidyl aminopeptidase, and the two synthetic proforms were also processed with the dipeptidyl aminopeptidase alone. From these experiments we conclude that the signal/leader peptidase cleaves the peptide bond between Ala-5 and Ala-4. This cleavage site is further substantiated by radio sequencing of procecropin A isolated after synthesis in a coupled system for in vitro transcription, translation, and processing. The two procecropins, which are stable to further digestion by the signal peptidase, are further processed by dipeptidyl aminopeptidase which removes, in two steps, the dipeptides Ala-Pro (residues -4 and -3) and Glu-Pro (residues -2 and -1). Although the synthetic peptide with only one dipeptide (Glu-Pro) preceding the mature cecropin sequence could function as a substrate for dipeptidyl aminopeptidase, it could be demonstrated as an intermediate in the enzymatic reaction with the procecropins. Dipeptidyl aminopoptidase did not cleave the procecropin analog when it was preceded by a single alanine residue, i.e. preprocecropin (-5,38). Antibacterial activity was demonstrated for the mature cecropin A-Gly obtained by processing of the synthetic preproprotein.

Amino Acid Sequence↗
PubMed1989

Identification of the promoter sequences involved in the interleukin-6 dependent expression of the rat alpha 2-macroglobulin gene.

The 5'-region of the rat alpha 2-macroglobulin gene has been characterized. A 5.6 kb Sal I - Xba I fragment containing the first 4 exons of the alpha 2-macroglobulin gene and 1.3 kb of its 5'-flanking region was sequenced. The putative transcriptional start site was determined by RNase protection and primer extension analysis. TATA- and CAAT-box equivalent sequences were found. A potential glucocorticoid receptor binding site was located on the antisense strand. DNA sequences containing the 5'-flanking region of the rat alpha 2-macroglobulin gene were linked to the gene coding for the bacterial chloramphenicol acetyltransferase and introduced into Hep G2 cells. In these transfected Hep G2 cells CAT activity could be induced by recombinant human interleukin-6. Deletion analyses have shown that the sequences between -852 and -777 as well as between -404 and -165 relative to the cap site, contain regulatory elements involved in the interleukin-6 dependent induction of the alpha 2-macroglobulin gene.

Amino Acid Sequence↗
PubMed1989

Comparative human pharmacology of low molecular weight heparins.

The pharmacodynamics of LMW heparins differ consistently from those of normal heparin. The relative bioavailability is greater than 90% and for some LMW heparins more than 100% after subcutaneous administration, as measured by the anti-Factor Xa activity. This indicates release of endothelial bound glycosaminoglycans with anti-Factor Xa-like activities. Direct determination of the LPL and HTGL activities demonstrate higher capacities of two and a lower capacity of three LMW heparins to release these enzymes from their endothelial glycoprotein receptors into the bloodstream. Thus, all LMW heparins are characterized by improved pharmacodynamics compared with normal heparin, but their anti-Xa to APTT and anti-Xa to anti-IIa ratios and half-lives differ among each other. The neutralization of the anticoagulant effects of LMW heparins by protamine are similar in vitro and in vivo at equigravimetric doses. However, unfractionated heparin and LMW heparins are not completely antagonized by protamine on a whole blood clotting test (thrombelastography). This inhibition of Factor Xa of LMW heparins is counteracted not completely by protamine. This may be due to a release of other glucosaminoglycans by LMW heparins. The present overview demonstrates that a comparative human pharmacology gives useful devices for prophylactic and therapeutic regimen for LMW heparins in patients in addition to the data obtained from animal models.

Animals↗
PubMed1989

Absence of significant interaction of fluconazole with cyclosporin.

The effect of a new azole antifungal drug, fluconazole, on cyclosporin concentration and pharmacokinetics was studied in ten bone marrow transplant recipients. There were no significant statistical or clinical differences in mean cyclosporin trough concentrations, peak concentrations and AUCs after fluconazole given either as a single 100 mg oral dose or as 100 mg daily for 14 days. Fluconazole was well tolerated without drug related side effects. Slight to moderate increases of liver laboratory parameters were observed in four patients during the multiple dose sequence, but these changes might be attributable, in part, to the underlying diseases or concomitant therapies. The data suggest a lack of clinically relevant pharmacokinetic interaction of fluconazole with cyclosporin. It is concluded that fluconazole may be administered to cyclosporin treated patients without enhanced risk of toxicity.

Adult↗
PubMed1989

Haemorheologic studies in patients with reduced coronary vasodilator capacity but normal coronary angiogram (syndrome X).

The cause of syndrome X, i.e. typical angina, positive exercise test, normal coronary angiogram, normal resting cardiac function, but reduced coronary vasodilator capacity is still unknown. The purpose of the study was to investigate blood fluidity as a possible cause of syndrome X. Haematocrit, plasma viscosity, erythrocyte aggregation, and erythrocyte deformability were examined in 14 patients with syndrome X (group 1), 24 patients with typical angina, positive exercise test, but normal coronary vasodilator capacity (group 2), and 37 patients with atypical chest pain and normal coronary arteries (control group). Coronary vasodilator capacity was determined by the argon method. Compared with normals, patients with syndrome X showed an elevated plasma viscosity (1.31 +/- 0.05 mPas vs 1.26 +/- 0.04 mPas, 2P less than 0.01), an elevated erythrocyte photometric aggregation index (141 +/- 27% vs 100 +/- 23%, 2P less than 0.01) and a reduced erythrocyte filterability (0.51 +/- 0.12 vs 0.66 +/- 0.09, 2P less than 0.01). Significant differences in the haemorheologic parameters between group 1, group 2 and the control group, however, were not detected. Multiple regression analysis did not reveal a significant relationship between coronary vasodilator capacity and the haemorheologic parameters tested. The data suggest that the reduction in coronary vasodilator capacity in patients with syndrome X cannot be attributed to haemorheologic alterations.

Adult↗
PubMed1989

Haemorrheological abnormalities in unstable angina pectoris: a relation independent of risk factor profile and angiographic severity.

Plasma viscosity, photometric erythrocyte aggregation index, and erythrocyte filterability were measured in 194 patients with coronary artery disease. Patients with unstable angina (n = 64) had a higher plasma viscosity and photometric erythrocyte aggregation index than patients with stable angina (95% confidence intervals for the mean difference: 0.052-0.100 mPa.s for plasma viscosity, and 43%-72% for the photometric erythrocyte aggregation index). Multiple regression with fibrinogen, cholesterol, high density lipoprotein cholesterol, triglycerides, blood pressure, smoking habits, coronary artery score, and left ventricular ejection fraction as independent variables showed a significant partial correlation between fibrinogen and the photometric erythrocyte aggregation index (r2 = 0.20) and plasma viscosity (r2 = 0.09), between triglycerides and plasma viscosity (r2 = 0.05), and between aortic pressure and erythrocyte filterability (r2 = 0.03). Logistic regression for unstable/stable angina with the haemorrheological variables as independent variables correctly identified 72% of the patients with stable angina and 78% of those with unstable angina. Inclusion of all the variables investigated did not substantially improve the discriminative potential of the logistic regression model. Unstable angina is associated with an impairment of blood fluidity that is essentially independent of risk factor profile and angiographic data.

Angina Pectoris↗
PubMed1989

Comparative study on a new one-stage clotting assay for heparin and its low molecular weight derivatives.

The effects of a normal and a low molecular weight (LMW) heparin fraction were compared by four coagulation methods. Plasma samples of patients were investigated who were treated with normal heparin or with a LMW heparin. The study was undertaken to analyze the interrelationship between the coagulation methods: Heptest, activated partial thromboplastin time, thrombin clotting time, and S 2222 chromogenic anti-factor Xa test. The results showed a high correlation between Heptest and S 2222 anti-factor Xa method for unfractionated and LMW heparin (r = 0.91 and 0.90). Comparing the coagulation times in seconds of Heptest and aPTT, the correlations were r = 0.56 (normal heparin) and 0.15 (LMW heparin). The correlation between the coagulation times of Heptest and thrombin clotting time were r = 0.65 and 0.25, respectively. The correlations between the coagulation methods were higher, when coagulation times rather than transformed values to units per liter of the Heptest and of the S 2222 anti-factor Xa method were employed. Furthermore, the data demonstrate a high sensitivity of the Heptest to conventional and LMW heparin, whereas activated partial thromboplastin time and thrombin clotting time are less sensitive to either heparin. For laboratory control of LMW heparin, Heptest and S 2222 chromogenic method are reliable tests. Therapeutic ranges will have to be established.

Blood Coagulation Tests↗
PubMed1989

[Cryptococcosis of the skin].

In a woman patient who had received a kidney transplant 9 years previously, we diagnosed a cryptococcosis of the skin on the right arm. The results of clinical and mycological investigations and the forms of treatment applied are discussed.

Cryptococcosis↗
PubMed1989

Long term anticoagulation with low molecular weight heparin in outpatients with side effects on oral anticoagulants.

A total of 70 outpatients with previous severe haemorrhages and other side effects on conventional oral anticoagulants given for prophylaxis of tromboembolism, were treated with low molecular weight (LMW) heparin fraction Kabi 2165. Anticoagulation was necessary in all patients because of recurrent venous thromboembolism (n = 39), artificial heart valve replacement (n = 12), atrial fibrillation with peripheral embolism (n = 10), and cardiomyopathy (n = 9). LMW heparin was injected sc at doses ranging from 2,500 to 15,000 antifactor Xa (aXa) units once daily by the patients themselves. The dose was adjusted on the basis of body weight, of bleeding risk, and risk of developing thromboembolism. Five of 70 patients with poor compliance, 3 experienced non fatal embolism during the treatment period. Two of 65 patients with good compliance experienced repeat embolism. No fatal embolism occurred. One major episode of gastrointestinal bleeding occurred in a patient with an undetected colon carcinoma. Nine minor hemorrhages were observed in all patients. The present experience suggests that LMW heparin may be used safely and effectively as an alternative anticoagulant in patients who have experienced bleeding and other complications with oral anticoagulants or conventional heparin.

Adult↗
PubMed1989

[The rabbit ear model as an acnegenicity test. 2. Effect of coal tar on follicle and sebaceous gland epithelium tumor induction].

Tar produced from hard coal was found to be acanthogenic to the interfollicular epiderm of rabbit ear skin and comedogenic to follicular epithelium in short-term (two weeks) and long-term (12 weeks) tests. Histological and autoradiographic experiments revealed a hyperproliferative effect in all cases in long-term tests. This contrasts with the atrophying effects reported by other authors. Tar application reduced the sebaceous gland area per follicle. Benignant epidermal tumours consisting of papillomas with a striking degree of sebaceous gland proliferation appeared on the rabbit ear skin after 8 weeks at the earliest.

Animals↗
PubMed1989

[Effects of gallopamil on iodine-123-phenyl-pentadecanoic acid and thallium 201 uptake in patients with coronary heart disease].

Numerous experimental and clinical studies indicated that in the presence of coronary artery stenoses, myocardial thallium-201 and free fatty acid uptake in poststenotic regions is reduced during exercise. The aim of this study was to investigate the effect of the calcium antagonist gallopamil on myocardial thallium-201 and free fatty acid uptake in patients suffering from coronary artery disease. In 6 patients with angiographically proven coronary artery disease--2 patients with 1-vessel, 2 patients with 2-vessel and 2 patients with 3-vessel disease--as well as good left ventricular performance and stable, exerciseinduced angina, quantitative double-tracer scintigraphy was performed. Patients were investigated after a placebo period of 1 week, after oral gallopamil medication for 4 weeks (3 X 50 mg gallopamil daily), and after a double-blind period of 1 week. During symptom-limited exercise, 2 mCi thallium-201 and 5 mCi iodine-123 phenyl-pentadecanoic acid (IPPA) were simultaneously injected intravenously. Immediately after exercise, as well as 1 and 4 hours later, planar images were obtained in ap, 30 degrees LAO and 60 degrees LAO projections. By means of a newly developed computer algorithm, global and regional myocardial tracer uptake as well as IPPA clearance were evaluated. - Gallopamil provoked a decrease of global myocardial thallium-201 and IPPA uptake due to a reduction of myocardial oxygen consumption. Regional thallium-201 and IPPA uptake as well as myocardial IPPA clearance in poststenotic areas tended to rise following gallopamil medication. Thus, in the presence of coronary artery disease, gallopamil provokes an improvement of regional perfusion (dilatation of larger coronary arterioles) as well as an enhanced free fatty acid utilization in reversibly ischemic myocardial regions.

Angina Pectoris↗
PubMed1988

[Effect of prostaglandin E1 on the formation of experimental arterial and venous thrombosis].

The effect of prostaglandin E1 on thrombus formation and haemostasis was investigated in a standardized experimental model in 20 rabbits. Arterial thrombus formation was reduced significantly by 70% and venous thrombosis by 68% in comparison with the controls. Collagen- and ADP-induced platelet aggregation was also inhibited significantly. Additionally, the time lag until onset of collagen-induced aggregation was significantly prolonged. Platelet count however, and plasma coagulation time showed no change. The data demonstrate a clear inhibition of arterial and venous thrombus formation, suggesting a powerful antithrombotic activity of prostaglandin E1. The effect may be explained by an influence on platelet function. The data further indicate that a full antithrombotic effect is achieved during prostaglandin E1 infusion.

Alprostadil↗
PubMed1988

Assembly of M13 and M13am8H1R1 procoat protein into microsomes is stimulated by rabbit reticulocyte lysate and ATP.

Processing of M13 procoat protein to transmembrane coat protein by dog pancreas microsomes is stimulated by a component of rabbit reticulocyte lysate and ATP. We asked whether this ATP-dependent reaction, involved in membrane assembly of procoat protein in the eukaryotic system, is related to the membrane potential dependent reaction observed for the membrane assembly of procoat protein in E. coli. Specifically, we asked if a mutant procoat protein which had been previously shown to be independent of the membrane potential with respect to its assembly in E. coli (M13am8H1R1 procoat protein) shows a stimulation by reticulocyte lysate and ATP in its assembly into microsomes. Since the mutant procoat protein behaved exactly as the wild type procoat protein in the eukaryotic in vitro system, we propose that the ATP-dependent reaction observed for the eukaryotic system does not substitute for the membrane potential dependent reaction in the prokaryotic system.

Adenosine Triphosphate↗
PubMed1988

Efficacy of intravenous prourokinase and a combination of prourokinase and urokinase in acute myocardial infarction.

Fifty-four patients with Q-wave acute myocardial infarction (AMI) were treated with heparin combined with intravenous single-chain urokinase-type plasminogen activator (prourokinase). To determine the optimal treatment regimen, prourokinase was applied in 3 different ways: group I received a bolus of 7.5 mg and a subsequent infusion of 40.5 mg over 60 minutes. Patency of the infarct artery was observed in 7 patients (50%) at the end of the infusion time. One hour after the end of the infusion the fibrinogen level had decreased to 87 +/- 12% of the preinfusion level; the plasminogen and alpha-2 antiplasmin levels to 61 +/- 13% and 59 +/- 34%, respectively. In group II prourokinase was administered as a 7.5 mg bolus followed by 66.5 mg over 60 minutes. Eleven patients (55%) had patent infarct-related coronary arteries and fibrinogen, plasminogen and alpha-2 antiplasmin levels had decreased to 58 +/- 29%, 38 +/- 18% and 21 +/- 14%, respectively. Group III was treated with a bolus of 3.7 mg prourokinase and 250,000 IU urokinase followed by 44.3 mg prourokinase, resulting in a patency rate of 65% (13 patients). Fibrinogen, plasminogen and alpha-2 antiplasmin levels decreased to 76 +/- 15%, 67 +/- 15% and 47 +/- 29%, respectively. Fibrin-specific thrombolysis can be achieved with glycosylated prourokinase. At higher dosages considerable systemic activation of the fibrinolytic system with little enhancement of the observed therapeutic effect occurred. The combination of prourokinase and urokinase yielded a higher patency rate than either dosage of prourokinase alone, although the difference was not statistically significant in this pilot trial.

Clinical Trials as Topic↗