Showing papers by "University of Bonn published in 1980"

Clinical Pharmacokinetics of Valproic Acid

Abstract: Valproic acid is rapidly absorbed from the gastrointestinal tract, peak concentrations being attained 1 to 2 hours after administration of the conventional tablet, but later with the enteric-coated tablets. The bioavailability of valproic acid is complete and independent of the preparation used. The apparent volume of distribution is relatively small (0.1 to 0.4 L/kg), due to high plasma protein binding. Protein binding is decreased in patients with renal insufficiency, in patients with chronic liver disease, and possibly in the presence of other displacing agents. The total plasma clearance of valproic acid is in the range of 5 to 10ml/min. Plasma elimination half-life is between 10 and 16 hours, and does not change after continued treatment with valproic acid alone. In combination therapy with other antiepileptic drugs, the half- life can be as short as 6 to 8 hours due to liver enzyme induction. Renal excretion of unchanged valproic acid accounts for only 1 to 3% of the total dose. Valproic acid is present in cerebrospinal fluid in concentrations equal to the unbound drug in plasma (around 10% of the total concentration). Valproic acid concentration in saliva is less than and unrelated to the free drug concentration in plasma. The drug is excreted into breast milk and evidence suggests that it also crosses the placenta. Four independent metabolic pathways — glucuronidation, β-oxidation and ω-oxidation (ω1, and ω2) have been demonstrated in man. Analytical difficulties caused by the similarity of the metabolites with many normal endogenous compounds and by chemical lability of several metabolites impede the isolation, identification and especially the quantification of valproic acid metabolites. Quantitative aspects of metabolism are essential for the understanding of drug effects in patients. The main metabolite 3-oxo-valproic acid shows comparable pharmacological activity to valproic acid itself in mice; unsaturated metabolites also show some activity. In young infants under 2 months of age valproic acid elimination half-life can be 60 hours, but in older children, plasma elimination appears to be identical to the adult situation. Valproic acid elimination is impaired in acute viral hepatitis and in liver cirrhosis. No information is available on valproic acid kinetics in renal insufficiency. Phenobarbitone plasma concentrations rise under combination therapy with valproic acid, because phenobarbitone elimination is impaired. Valproic acid lowers total plasma concentrations of phenytoin by displacing it from its plasma albumin binding site, but free phenytoin concentrations remain unchanged and phenytoin doses need not be modified. Valproic acid elimination is enhanced in the presence of inducing drugs like phenobarbitone, primidone, phenytoin and carbamazepine. The valproic acid dose-plasma concentration relationship is curvilinear, since valproic acid protein binding decreases with higher concentrations. Therefore, the increase in the plasma concentration is smaller than expected from the dose increase. The lower value of the therapeutic plasma concentration range of valproic acid is around 50μg/ml. Because of low clinical toxicity the upper value of the therapeutic range has yet to be determined.

On the boundary value problem of the biharmonic operator on domains with angular corners

Abstract: The paper is concerned with boundary singularities of weak solutions of boundary value problems governed by the biharmonic operator. The presence of angular corner points or points at which the type of boundary condition changes in general causes local singularities in the solution. For that case the general theory of V. A. Kondrat'ev provides a priori estimates in weighted Sobolev norms and asymptotic singular representations for the solution which essentially depend on the zeros of certain transcendental functions. The distribution of these zeros will be analysed in detail for the biharmonic operator under several boundary conditions. This leads to sharp a priori estimates in weighted Sobolev norms where the weight function is characterized by the inner angle of the boundary corner. Such estimates for “negative” Sobolev norms are used to analyse also weakly nonlinear perturbations of the biharmonic operator as, for instance, the von Karman model in plate bending theory and the stream function formulation of the steady state Navier-Stokes problem. It turns out that here the structure of the corner singularities is essentially the same as in the corresponding linear problem.

African environmental and climatic changes and the general atmospheric circulation in late pleistocene and holocene

Abstract: The paper describes the environmental and climatic changes which took place in Africa from the late Pleistocene through the Holocene and the general atmospheric circulation patterns which likely correspond to them. Three major periods are considered: (1) a period of aridity and dune building c. 20,000-12,000 B.P. in which the Sahara advanced considerably southward; (2) a moist, lacustrine period c. 10,000-8,000 B.P.; and (3) a second moist, lacustrine period toward c. 6,500-4,500 B.P. in which the entire Sahara desert contracted considerably. The prevailing atmospheric circulation patterns are theorized on the basis of corresponding changes of surface boundary conditions-primarily changing thermal character—and known dynamic behavior of the atmosphere.

Characterization of adenosine receptors in rat brain by (-)[3H]N6-phenylisopropyladenosine.

Abstract: (−)N6-Phenylisopropyladenosine, a potent agonist in adenosine-responsive cellular systems, has been labeled with tritium to high specific activity (26 Ci/mmol) and used to identify adenosine binding sites in rat brain membranes. (−)[H3]N6-Phenylisopropyladenosine binding was studied by a vacuum filtration technique. The binding was rapid, rapidly reversible, dependent on pH and temperature and stereospecific since the (−)isomer of N6-phenylisopropyladenosine was 40-fold more potent than the (+)isomer in competition experiments. The stereospecific binding sites were saturable and bound 0.8 pmol of (−)N6-phenylisopropyladenosine per mg of membrane protein. The dissociation constant (KD) of (−)N6-phenylisopropyladenosine for these sites was 5–12 nM as determined independently by saturation and kinetic binding studies. Endogeneous ligands seem to occupy the binding sites since pretreatment with adenosine deaminase increased the specific binding. Adenosine and several adenosine derivatives were studied for their ability to compete with (−)[3H]N6-phenylisopropyladenosine binding. (−)N6-Phenylisopropyladenosine-5′-monophosphate, N6-phenyladenosine, N6-benzyladenosine, 2-chloroadenosine and adenosine were most potent in displacing the radioligand from its binding sites and the IC50-values ranged from 0.3–7 μM. Physiologically inactive compounds such as inosine, hypoxanthine, adenine and the ribose-modified analogues 2′-deoxyadenosine and 2′,5′-dideoxyadenosine did not substantially inhibit binding at concentrations up to 100 μM. The adenosine antagonists isobutylmethylxanthine (IC50 3.2 μM), theophylline (IC50 7.6 μM) and caffeine (IC50 99 μM) competed for the binding sites of (−)[3H]N6-phenylisopropyladenosine in a manner which parallels their known pharmacological activity whereas other phosphodiesterase inhibitors were ineffective. The (−)[3H]N6-phenylisopropyladenosine binding sites in rat brain membranes appear to be equivalent to adenosine receptor sites on the cell surface which have recently been classified as R-site adenosine receptors.

Reducibility of generalized principal series representations

Abstract: (normalized induction) a generalized principal series representation. When v is unitary, these are the representations occurring in Harish-Chandra's Plancherel formula for G; and for general v they may be expected to play something of the same role in harmonic analysis on G as complex characters do in R n. Langlands has shown tha t any irreducible admissible representation of G can be realized canonically as a subquotient of a generalized principal series representation (Theorem 2.9 below). For these reasons and others (some of which will be discussed below) one would like to understand the reducibility of these representations, and it is this question which motivates the results of this paper. We prove

On the finite element approximation of the nonstationary Navier-Stokes problem

Abstract: In this note we report some basic convergence results for the semi-discrete finite element Galerkin approximation of the nonstationary Navier-Stokes problem Asymptotic error estimates are established for a wide class of so-called conforming and nonconforming elements as described in the literature for modelling incompressible flows Since the proofs are lengthy and very technical the present contribution concentrates on a precise statement of the results and only gives some of the key ideas of the argument for proving them Complete proofs for the case of conforming finite elements may be found in a joint paper of J Heywood, R Rautmann and the author [5], whereas the nonconforming case will be treated in detail elsewhere

The upper atmosphere of Venus during morning conditions

Abstract: The structure and composition of the Venus upper atmosphere between 130- and 650-km altitude were measured for a solar zenith angle of approximately 60 deg by the neutral gas mass spectrometer on board the Pioneer Venus multiprobe bus. Below 180 km a wavelike structure is quite evident in the CO2 and He number density profiles. For altitudes above 100 km a one-dimensional model of the Venus upper atmosphere during morningside conditions (MS model) is presented. Number densities at 150-km altitude are as follows: CO2 equals 4.2 x 10 to the 9th, N2 equals 1.1 x 10 to the 9th, CO equals 2.8 x 10 to the 9th, and He equals 4.8 x 10 to the 6th per cu cm. The homopause altitudes for N2 and He are at 136 and 130 km, respectively.

Ligandstruktur und Komplexierung, L. Ionenselektive Farbstoffkronenether

Abstract: Neue Farbstoffe wurden synthetisiert, die ein ionenselektives Kronenethersystem enthalten, bei dessen Komplexierung mit Kationen der Chromophor im Grund- und angeregten Zustand elektronisch unterschiedlich beeinflust wird. Verschiedene Ionentypen rufen verschiedene Farbanderungen hervor. Auser cyclischen Kronenethern mit Chromophoren vom Typ der Azofarbstoffe (1 – 3, 8a, b, 22, 24), des Naphtholblaus (10), des Phenolblaus (11), der Stilbenfarbstoffe (14a, b), der (Mero-)Cyanine (16, 17a, b) und des Konigschen Salzes (19, 20) werden auch an offenkettige Oligoethylenglycolether-Ketten gebundene Chromophore (9, 18) beschrieben. Die teilweise betrachtlichen Anderungen der UV/vis-Absorption einiger Farbstoffe mit Komplexbeteiligung des Auxochroms wie des Antiauxochroms werden erortert. Ligand Structure and Complexation, L. Ion-selective Crown Ether Dyes New dyes with an ion-selective crown ether system, the complexation of which with cations influences the ground and excited states of the chromophore to a different extent, have been synthesized. Different types of alkali/alkaline earth metal ions cause different colour changes, significant effects being normally observed with cations fitting selectively into the crown ether units with chromophores of azo dyes (1 – 3, 8a, b, 22, 24), naphthol blue (10), phenol blue (11), stilbene dyes (14a, b), der (mero-)cyanines (16, 17a, b), and of Konig's salt (19, 20). Chromophores bound to open chain oligoethylene glycol ethers are also described. The remarkable changes of light absorption in the course of complexation of some of the dyes are discussed in terms of donor participation of the auxochrome or antiauxochrome.

Charge density in anhydrite, CaSO4, from X-ray and neutron diffraction measurements

Abstract: The room-temperature electron-density distribution in natural anhydrite, CaSO4, has been studied by both X-ray and neutron diffraction. Conventional refinements of the data sets yielded RXw -0.020 and RNw = 0.025. The X-ray intensities were also used for high-order refinements, a refinement based on a point-charge model for the representation of positive residual charge accumulations, and a multipole expansion refinement. All these refinements were performed to study and to reduce parameter bias arising from bonding effects. The multipole expansion model yielded the significantly improved R w = 0.0116. The resulting (X--X) and (X-N) dynamic deformation density maps showed features qualitatively in agreement. Special attention was given to the charge distribution within and around the [SO4] 2anion. The observed bond density distribution is different from earlier results obtained from comparable sulfate derivatives and from the [8206 ]2anion, indicating a considerable 3d population of the S atom.

Anaerobic oxidation of thiosulfate and elemental sulfur in Thiobacillus denitrificans

Abstract: Thiobacillus denitrificans strain RT could be grown anaerobically in batch culture on thiosulfate but not on other reduced sulfur compounds like sulfide, elemental sulfur, thiocyanate, polythionates or sulfite. During growth on thiosulfate the assimilated cell sulfur was derived totally from the outer or sulfane sulfur. Thiosulfate oxidation started with a rhodanese type cleavage between sulfane and sulfone sulfur leading to elemental sulfur and sulfite. As long as thiosulfate was present elemental sulfur was transiently accumulated within the cells in a form that could be shown to be more reactive than elemental sulfur present in a hydrophilic sulfur sol, however, less reactive than sulfane sulfur of polythionates or organic and inorganic polysulfides. When thiosulfate had been completely consumed, intracellular elemental sulfur was rapidly oxidized to sulfate with a specific rate of 45 natom S°/min·mg protein. Extracellularly offered elemental sulfur was not oxidized under anaerobic conditions.

Siegel's modular forms and the arithmetic of quadratic forms

Abstract: Recently many authors utilized indefinite quadratic forms and Weil's representations to construct automorphic forms with Euler products on metaplectic groups or on orthogonal groups. For example, Shintani [27] employed indefinite quadratic forms of signature (2, 1) and associated Weil's representations to construct automorphic forms on the metaplectic group of genus 1, answering to a question raised by Shimura [26]. His results were modulated and generalized by Niwa [17], Gelbart [-8], Oda [18] and Rallis [20]. Howe [10] has given conjectures in most general cases. In this paper, we shall be concerned with definite quadratic forms of four variables and associated Weil's representations to construct Siegel's modular forms of genus 2. More precisely, we shall construct a Siegel modular form of genus 2, which is an eigenfunction of Hecke operators, from a pair of automorphic forms on a definite quaternion algebra over Q or from an automorphic form on a totally definite quaternion algebra over a real quadratic field. To avoid excessive overlaps with the text, we shall explain our result in the simplest case. Let D be a definite quaternion algebra over Q of discriminant d 2 and R be a maximal order of D. Let D~ denote the adelization of D • For a rational prime p, we put R p = R | p and let H denote the Hamilton quaternion algebra. We set K = I I R~ x H • Let q01 and ~02 be complex valued functions on p D~ which are left D • and right K-invariant. For every rational prime p.~d, we can define the action of Hecke operator T'(p) on qh (i= 1, 2) in the same manner as in Well [33]. We assume that T'(p)~0i=2~(p)qh, 2/(p)EC(i=I, 2) if n p,t/d. Let D~ = U D • y~K be a double coset decomposition of D~, where H is i= l the class number of D. We can assume that the reduced norm of Yi is 1 (1 N i < H). For l

On the symmetric travelling salesman problem: Solution of a 120-city problem

Abstract: The polytope associated with the symmetric travelling salesman problem has been intensively studied recently (cf. [7, 10, 11]). In this note we demonstrate how the knowledge of the facets of this polytope can be utilized to solve large-scale travelling salesman problems. In particular, we report how the shortest roundtrip through 120 German cities was found using a commercial linear programming code and adding facetial cutting planes in an interactive way.

The coding of auditory signals in the torus semicircularis of the fire-bellied toad and the grass frog: Responses to simple stimuli and to conspecific calls

Abstract: The function of the anuran midbrain auditory nucleus was studied by recording the responses of single cells in the torus semicircularis of the grass frog (Rana t temporaria L) and the fire-bellied toad (Bombina bombina (L)) to single tone pulses, combinations of two tones, white noise, and tape-recorded conspecific calls About 50% of the auditory neurons in the midbrain of the fire-bellied toad, and 60–70% of those in the grass frog, are spontaneously active In winter the proportion of spontaneously active cells is lower The frequencies of spontaneous discharge are between 01 and 153 impulses/s The basic tonic and phasic responses, either excitation or inhibition, are frequently combined to form response patterns The distribution of characteristic frequencies among the units studied matches the frequency spectrum of the calls Sharpness of tuning varied widely, Q10dB ranging from 029 to 45 with one exception (75 in one neuron) The threshold curves are usually V-shaped but can also have the shape of a W In some cases the response region is confined to a continuous area on the frequency-intensity surface; in others there may be separate areas, within which opposite responses are elicited The intensity characteristics can be classified into two main types with roughly equal frequency of occurrence — teadily rising or saturating curves, and curves decaying from a maximum on either side of the most effective SPL Latencies were very short (5–10 ms) in some cases, but responses could occur with latencies as long as 300 ms The optimal repetition rates for pulses at the best frequency are consistent with the temporal structure of the conspecific calls About 50% of the units studied in the toad and about 75% of those in the frog responded to the conspecific calls Some of the neurons gave different responses to the different calls, ranging from gradation in magnitude to opposite reactions A few units responded exclusively to the release calls In most cases the responses to the calls were consistent with those to the simple artificial stimuli Magnitude gradation, opposite responses to different calls and selective responses could be ascribed primarily to the tuning characteristics of the units In some cases, however, the temporal structure of the call was the critical parameter

Effects of verapamil on P-R-intervals in relation to verapamil plasma levels following single i.v. and oral administration and during chronic treatment

Abstract: A close relationship between verapamil plasma concentration and effect on P–R interval could be established both after single iv and oral administration and during chronic oral treatment After iv administration a linear relationship between verapamil plasma concentration and Δ P–R (y=x (074)+18) with a small between subject variation in the slope of the regression (%coefficient of variation 187, range 071–110) was observed The slope of the oral plasma concentration response regression (y=x (033)−30) was statistically significantly (p<005) less than the slope of the iv plasma level response regression Interindividual variation in the slope was most pronounced (range 013 to 047) On average two to three times higher verapamil plasma levels were required after oral administration in order to produce the same increase in Δ PR as after intravenous administration The most plausible explanation for the different slopes of the plasma level response regression seems to be stereo-selective presystemic elimination Since after oral administration the plasma level response curve is less steep than after iv administration this indicates that the more active l-isomer is preferentially metabolized during hepatic first-pass metabolism

The biological significance of atypical hyperplasia of the prostate

Abstract: In tissue biopsies and resection material (TUR) of the prostate a high coincidence (49.4%) was found between atypical primary hyperplasia with atypical-dysplastic microglandular, adenomatous and cribriform structures on the one hand and carcinomas on the other. The frequency of atypical hyperplasia in prostatic tissue without carcinoma was 2.8%. Microglandular pattern predominates in atypical hyperplasia combined with differentiated adenocarcinomas. A high coincidence between cribriformly structured glands of atypical primary hyperplasia and solid anaplastic — cribriform carcinomas can be observed. Autoradiographically the labeling index of atypical hyperplasia was three times as high as that of simple hyperplasia. The mean labeling index of atypical hyperplasia, however, was similar to that of poorly differentiated adenocarcinomas and cribriform carcinomas. The similar proliferation pattern of atypical hyperplasia and carcinomas as well as the high coincidence between both indicate that severe atypical primary hyperplasia is a precancerous lesion. Therefore, those patients with primary atypical hyperplasia with distinct cellular and structural atypia but without manifest carcinomas in prostatic biopsy or resection material should be followed up at short intervals.

Measurements of the Venus lower atmosphere composition: A comparison of results

Abstract: The data from seven gas analyzer measurements obtained from Pioneer Venus and the Venera 11 and 12 spacecraft are compared, and the chemical composition of the atmosphere from approximately 700 km to the surface is examined. In and near the clouds, the O2 mixing ratio is a few ten ppm, and the CO mixing ratio is 20-30 ppm. The existence of COS in the lower part of the atmosphere is doubtful, and its mixing ratio at higher altitudes does not exceed a few ppm. SO2 may exist below the clouds at a mixing ratio of about 100 ppm, whereas in the clouds it is less than 10 ppm. A discrepancy in the data still exists for the measurement of the water vapor abundance.

Effects of prolonged omnilateral gravistimulation on the ultrastructure of statocytes and on the graviresponse of roots.

Abstract: Statocytes of vertically growing roots of Lepidium sativum L. exhibit a strict polarity: The nucleus is positioned near the proximal periclinal cell wall, amyloplasts are sedimented on a complex of rough endoplasmic reticulum (ER) consisting of parallel cisternae near the distal periclinal cell wall.