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Showing papers by "University of Bonn published in 1982"



Journal ArticleDOI
TL;DR: In studies on absorption, benzylpenicillin absorption was not disturbed by Cimetidine in most cases, but a several-fold increase in urinary excretion occurred repeatedly in I subject, indicating that increased absorption of acid-labile compounds may occur in some patients.
Abstract: Because of widespread (and often uncritical) use of Cimetidine, there is considerable potential for interactions to occur with other drugs. In studies on absorption, benzylpenicillin absorption was not disturbed by Cimetidine in most cases, but a several-fold increase in urinary excretion occurred repeatedly in I subject, indicating that increased absorption of acid-labile compounds may occur in some patients. The absorption of ketoconazole was reduced by more than half with Cimetidine, a consequence of its poor water solubility which is enhanced in acid solution. Conflicting results are reported with tetracycline, the overall absorption of which does not appear to be significantly altered by Cimetidine. Aspirin absorption was halved by Cimetidine in 3 of 6 subjects, when the intragastric pH was raised above 3.5. Cimetidine did not affect the absorption of ampicillin, co-trimoxazole or prednisolone. Cimetidine has been shown to inhibit various microsomal drug-metabolising enzymes in animal as well as human liver, most likely through the binding of the imidazole ring structure of Cimetidine to the haeme moiety of cytochrome P-450. In 7 studies, Cimetidine uniformly prolonged antipyrine half-life by 18 to 37% and reduced its clearance by 10 to 27%. After chronic dosing with Cimetidine, warfarin clearance was reduced from 3.4 to 2.5ml/min, whilst the volume of distribution and elimination half-life remained unchanged. Steady-state warfarin concentrations, as well as Prothrombin times, increased upon addition of Cimetidine to the treatment regimen. Warfarin concentration and effect both returned to pre-Cimetidine values when Cimetidine was withdrawn. Amongst the benzodiazepines, diazepam, desmethyldiazepam and chlordiazepoxide plasma clearance values were reduced by Cimetidine by 43, 28 and 63 %, respectively, and half-lives increased accordingly, while volumes of distribution and protein binding were not affected. Long term treatment with Cimetidine and diazepam resulted in a 30 to 80% increase in steady-state diazepam concentrations. In contrast, the pharmacokinetics of oxazepam and lorazepam, which are eliminated almost entirely by glucuronidation and not oxidation, were not altered by Cimetidine. Cimetidine also inhibits the metabolism of phenytoin, theophylline and carbamazepine. A single dose of Cimetidine decreased indocyanine green clearance by 23%, which was interpreted as a reduction in hepatic blood flow. The area below the Propranolol concentration-time curve (oral administration) was increased by between 25 and 60 % with Cimetidine and by 25 % after intravenous administration of Propranolol, with no change in elimination half-life, volume of distribution or bioavailability. With chronic oral Propranolol dosing, Cimetidine increased the steady-state concentration from 23.2 to 44.9ng/ml. The bioavailability of labetalol almost doubled from 30 to 54 % with Cimetidine, with no change in half-life and systemic clearance. The oral clearance and elimination half-life of chlormethiazole was increased by 30 and 50%, respectively, by Cimetidine. Studies with high hepatic clearance drugs have not consistently shown cimetidine-induced changes in systemic clearance (liver blood flow dependent), but oral clearance increased in all cases, consistent with inhibition of drug metabolism. Peculiarities of Cimetidine effect on drug metabolism are (a) only about 20% of a Cimetidine dose is metabolised in man, as compared with a much larger fraction with other inhibitory drugs; (b) the maximum effect attained occurs within I day whereas offset of effect varies with individual interacting drugs; (c) the degree of inhibition of metabolism is much more pronounced in patients with already impaired liver function (i.e. liver disease). Antacids of a weak neutralising capacity (10 to 15mmol/dose) did not influence the absorption of Cimetidine. However, antacids (aluminium plus magnesium hydroxide) with a neutralising capacity between 26 and 41 mmol/10ml reduced the bioavailability of Cimetidine by 20 to 35%. A recent study with an aluminium plus magnesium hydroxide antacid of 70mmol/10ml did not affect Cimetidine bioavailability. The antacid preparation used differed from others by a disproportionate increase in the aluminium hydroxide content. Metoclopramide and propantheline also reduced the absorption of Cimetidine by an average of 20 %, indicating the importance of gastric emptying for Cimetidine absorption. Phenobarbitone administration over 3 weeks led to an increase in Cimetidine plasma clearance by 18%, mainly due to an increase in the non-renal clearance, but probably also partially due to a reduction in Cimetidine absorption. The most important clinical consequences of interactions with Cimetidine primarily involve inhibition of drug metabolism. Clinically important interactions are predominantly manifested in those drugs which have a narrow therapeutic index (e.g. Phenytoin, warfarin, theophylline). The interaction leads to higher steady-state blood concentrations and hence increases the incidence of side effects and toxicity. Adverse effects of such interactions can be avoided by careful monitoring and adjustment of dosage for those drugs which undergo phase I metabolic detoxification in the liver when it is necessary to administer such drugs concomitantly with Cimetidine.

243 citations


Journal ArticleDOI
Dieter Bös1
TL;DR: In this paper, a simple model of the "tax state" where a progressive income tax is used to finance publicly supplied goods that are distributed free of charge is presented, and the individual citizens may be dissatisfied with such a fiscal system.
Abstract: This paper presents a simple model of the ‘tax state’, where a progressive income tax is used to finance publicly supplied goods that are distributed free of charge. The individual citizens may be dissatisfied with such a fiscal system. If more than 50% are dissatisfied, we speak of a ‘crisis of the tax state’.

232 citations




Journal ArticleDOI
TL;DR: It was observed that 4-hydroxylation of debrisoquine and N-oxidation of sparteine, the metabolic processes removing most of the drug from the body, were grossly impaired or nearly absent in some subjects, and the recent finding that non- and poor metaboliser subjects have an impaired capacity to carry out stereospecific E-10-hydrogenation of nortriptyline might suggest monogenic control of this benzylic hydroxylated reaction.
Abstract: Until quite recently, pharmacogenetic polymorphisms in oxidative drug metabolism were considered rare. However during the last years several monogenically determined poly of oxidative reactions in drug metabolism involving benzylic hydroxylation of debrisoquine, N-oxidation of sparleine, C-hydroxylation of tolbutamide, O-de-ethylation of phenacetin, p-hydroxylation of Phenytoin and mephenytoin and N-glucosidation of amylobarbitone (amobarbital) have been discovered. The incidence of these various pharmacogenetic conditions varies between 2 and 9 % of the population. Among these conditions the best studied examples are the polymorphic oxidation of debrisoquine and sparteine.

205 citations


Journal ArticleDOI
TL;DR: The observed cleavage of cathepsin D precursor in vitro resembles the autocatalytic activation of pepsinogen.
Abstract: Precursors of cathepsin D and β-hexosaminidase were isolated from secretions of human fibroblasts and their activity was studied with natural substrates. The immunoprecipitated precursor of cathepsin D, Mr 53000, was inactive with radioactive hemoglobin as substrate. At pH 3.8–4.2 an activation of the precursor took place, which was correlated by a reduction in size to Mr 51 500. The observed cleavage of cathepsin D precursor in vitro resembles the autocatalytic activation of pepsinogen. The precursor of β-hexosaminidase A is able to cleave the natural substrate GM2 ganglioside. This reaction, like that of the mature enzyme, depends on the presence of a protein activator, which interacts with the substrate and the enzyme.

164 citations


Journal ArticleDOI
TL;DR: In this article, a crossover study showed that the polymorphic Noxidation of sparteine and 4-hydroxylation of debrisoquine are related pharmacogenetic entities; the metabolism of the two drugs is regulated by identical or closely related genetic factors.
Abstract: Thirty-eight healthy subjects were given single oral doses of debrisoquine and sparteine in a crossover study. The close correlation between urinary metabolic ratios of the two drugs (rs = 0.91; P less than 0.001) demonstrates that the polymorphic N-oxidation of sparteine and 4-hydroxylation of debrisoquine are related pharmacogenetic entities; the metabolism of the two drugs is regulated by identical or closely related genetic factors.

155 citations


Journal ArticleDOI
26 Aug 1982-Nature
TL;DR: It is demonstrated that the C4A and C4B locus-encoded α-chains have a molecular weight (MW) of 96,000 and 94,000, respectively, presenting for the first time a molecular basis for the difference between all C 4A andC4B variants tested.
Abstract: The major histocompatibility complex (MHC)-linked fourth component of complement (C4) shows a high degree of polymorphism in several animal species1–4. In man C4 polymorphism was detected by distinct charge differences of the variants5–7. O'Neill et al.8 showed that this C4 polymorphism was controlled by two closely linked genetic loci, F (C4A) and S (C4B) and these results were extended by Awdeh et al.9 with an improved typing method. Biochemical analysis of human C4 has revealed that it consists of three polypeptide chains, α, β and γ10. In all reports so far on the molecular analysis of human C410–13, no molecular weight differences between the A and B locus-encoded molecules have been noticed. Here we demonstrate that the C4A and C4B locus-encoded α-chains have a molecular weight (MW) of 96,000 and 94,000, respectively, presenting for the first time a molecular basis for the difference between all C4A and C4B variants tested. Even rare variants that are difficult to allocate to the A or B locus on the basis of charge differences14,15 could be identified as C4A or C4B variants in this way, thereby providing new insights into the relationships between the C4A and C4B loci.

150 citations


Journal ArticleDOI
TL;DR: It could be shown with three different techniques that the activator protein extracts glycolipid monomers from micelles or liposomes to give water-soluble complexes with a stoichiometry of 1 mol of glycolIPid/mol of activatorprotein.
Abstract: The lysosomal degradation of ganglioside GMZ by hexosaminidase A depends on the presence of the specific activator protein which mediates the interaction between micellar or membrane-bound ganglioside and water-soluble hydrolase. The mechanism and the glycolipid specificity of this activator were studied in more detail. 1 It could be shown with three different techniques (isoelectric focusing, centrifugation and electrophoresis) that the activator protein extracts glycolipid monomers from micelles or liposomes to give water-soluble complexes with a stoichiometry of 1 mol of glycolipid/mol of activator protein. Liposome-bound ganglioside Gm2 is considerably more stable against extraction and degradation than micellar ganglioside. 2 In the absence of enzyme the activator acts in vitro as glycolipid transfer protein, transporting glycolipids from donor to acceptor membranes. 3 The activator protein is rathcr specific for ganglioside GM2. Other glycolipids (GM3, GM1, GDla and GA2) form less stable complexes with the activator and are transferred at a slower rate (except for ganglioside G, than ganglioside GM2.

149 citations


Journal ArticleDOI
TL;DR: In this paper, a general bosonic construction of oscillator-like unitary irreducible representations (UIR) of non-compact groups whose coset spaces with respect to their maximal compact subgroups are Hermitian symmetric is given.
Abstract: We give a general bosonic construction of oscillator-like unitary irreducible representations (UIR) of non-compact groups whose coset spaces with respect to their maximal compact subgroups are Hermitian symmetric. With the exception of E7(7), they include all the non-compact invariance groups of extended supergravity theories in four dimensions. These representations have the remarkable property that each UIR is uniquely determined by an irreducible representation of the maximal compact subgroup. We study the connection between our construction, the Hermitian symmetric spaces and the Tits-Koecher construction of the Lie algebras of corresponding groups. We then give the bosonic construction of the Lie algebra ofE7(7) in SU(8), SO(8) and U(7) bases and study its properties. Application of our method toE7(7) leads to reducible unitary representations.

Journal ArticleDOI
TL;DR: A finite element method for approximating elliptic equations on domains with corners is proposed, which makes use of the singular functions of the problem in the trial space and the kernel functions in the test space to lead to good approximates of the coefficients ofThe singular functions.
Abstract: A finite element method for approximating elliptic equations on domains with corners is proposed. The method makes use of the singular functions of the problem in the trial space and the kernel functions of the adjoint problem in the test space. This leads to good approximates of the coefficients of the singular functions. In the numerical computations, the method is compared with the well known Singular Function Method.

Journal ArticleDOI
TL;DR: The Ca 2+ ionophore A23187 consistently induced the exit of Toxoplasma gondii trophozoites from cultured macrophages which they had recently infected and was enhanced by the addition of ethylene glycol bis(β-aminoethyl ether) N,N,N −tetraacetic acid (EGTA) in the reaction mixture.

Journal ArticleDOI
TL;DR: In this article, the clinical and morphological findings of 27 children with nephronophthisis were described, including polyuria-polydipsia, hyposthenuria, anemia, growth retardation, and azotemia with progressive renal failure.
Abstract: The clinical and morphological findings are described in 27 children with nephronophthisis. Seventeen children were considered as sporadic cases. In 10 familial cases the presumed mode of inheritance was autosomal recessive. The clinical picture was rather uniform: polyuria-polydipsia, hyposthenuria, anemia, growth retardation, and azotemia with progressive renal failure. Six patients presented with tapeto-retinal degeneration. In a further seven children other ocular changes were detected. Two female siblings showed additional non-renal manifestations: mental retardation, pulmonary emphysema, skeletal anomalies, and congenital hepatic fibrosis.

Journal ArticleDOI
TL;DR: In this article, a simple statistical ray analysis is employed to analyze the observed fluctuations of the electron content and Faraday rotation in the solar corona, and it is shown that the observed rotation fluctuations cannot be solely due to electron density fluctuations in the corona unless the coronal magnetic field is some 5 times stronger than suggested by current estimates.
Abstract: The 229 GHz S band carrier signals of the two Helios spacecraft are used to probe the magnetic and density structures of the solar corona inside 005 AU In this paper we analyze the observed fluctuations of the electron content and Faraday rotation A simple statistical ray analysis is employed We conclude that (1) the observed Faraday rotation fluctuations cannot be solely due to electron density fluctuations in the corona unless the coronal magnetic field is some 5 times stronger than suggested by current estimates, and (2) the observed Faraday rotation fluctuations are consistent with the hypothesis that the sun radiates Alfven waves with sufficient energies to heat and accelerate high-speed solar wind streams

Journal ArticleDOI
TL;DR: In this paper, the pattern of naturally occurring electric currents around 1-day-old primary roots of Lepidium sativum L. growing vertically downward and the current pattern following gravistimulation of the root has been examined.
Abstract: Using a highly sensitive vibrating electrode, the pattern of naturally occurring electric currents around 1-day-old primary roots of Lepidium sativum L. growing vertically downward and the current pattern following gravistimulation of the root has been examined. A more or less symmetrical pattern of current was found around vertically oriented, downward growing roots. Current entered the root at the root cap, the meristem, and the beginning of the elongation zone and left the root along most of the elongation zone and in the root hair zone. After the root was tilted to a horizontal position, we observed current flowing acropetally at the upper side of the root cap and basipetally at the lower side within about 30 seconds in most cases. After a delay of several minutes, acropetally oriented current was also found flowing along the upper side of the meristematic zone. The apparent density of the acropetal current in the root cap region increased and then decreased with time. Gravitropic curvature was first visible approximately 10 minutes after tilting of the root to the horizontal position. Since the change in the pattern of current in the root cap region precedes bending of the root and is different for the upper and lower side, a close connection is suggested between the current and the transduction of information from the root cap to the elongation zone following graviperception in the cap.

Journal ArticleDOI
TL;DR: In this article, the elastic electron-neutron cross sections were measured at values of the square of four-momentum transfer (Q/sup 2/) of 2.5, 4.0, 6.0 (GeV/c)/sup 2/ using a deuterium target and detecting the scattered electrons at 10/sup 0/
Abstract: The elastic electron-neutron cross sections were measured at values of the square of four-momentum transfer (Q/sup 2/) of 2.5, 4.0, 6.0, 8.0, and 10.0 (GeV/c)/sup 2/ using a deuterium target and detecting the scattered electrons at 10/sup 0/. The ratio of neutron to proton elastic cross sections decreases with Q/sup 2/. At high Q/sup 2/ this trend is inconsistent with the dipole law, form-factor scaling, and many vector dominance models, although it is consistent with some parton models.

Journal ArticleDOI
TL;DR: The pathways of photolithotrophic sulphur oxidation in Chlorobiaceae, Chromatiaceae and Rhodospirillaceae are separately compiled under evaluation of the presently available data.
Abstract: Most phototrophic bacteria use reduced inorganic sulphur compounds as electron donors during anoxygenic photosynthesis. Principally, sulphide is oxidized via sulphite to sulphate. Elemental sulphur may appear as intermediary storage product (inside: Chromatium, Thiocapsa; outside: Chlorobium, Ectothiorhodospira; not in: Rhodopseudomonas sulfidophila). Adenosine phosphosulphate is an intermediate in sulphite oxidation by Chromatium, Thiocapsa and Chlorobium. Thiosulphate undergoes splitting to sulphide (or elemental sulphur) and sulphite, or is oxidized to tetrathionate. Sulphide may be oxidized to elemental sulphur by cytochrome c or to thiosulphate (perhaps sulphite?) by flavocytochrome c, or to sulphite by a reverse (sirohaem) sulphite reductase. The latter enzyme also oxidizes polysulphides and probably elemental sulphur. Sulphite is either oxidized by APS reductase to form adenosine phosphosulphate - from which sulphate is released by ADP sulphurylase - or by sulphite: acceptor oxidoreductase directly to sulphate. The electron acceptor of most of these oxidative enzymes are cytochromes or non-haem iron-sulphur proteins. The pathways of photolithotrophic sulphur oxidation in Chlorobiaceae, Chromatiaceae and Rhodospirillaceae are separately compiled under evaluation of the presently available data.

Journal ArticleDOI
TL;DR: In this paper, the authors prove a-priori estimates for harmonic mappings between Riemannian manifolds which solve a Dirichlet problem, which depend only on geometric quantities, namely curvature bounds, injectivity radii, and dimensions.
Abstract: In this paper, we prove a-priori estimates for harmonic mappings between Riemannian manifolds which solve a Dirichlet problem. These estimates employ geometrical methods and depend only on geometric quantities, namely curvature bounds, injectivity radii, and dimensions. An essential tool is the introduction of almost linear functions on Riemannian manifolds. Furthermore, we show the existence of almost linear and harmonic coordinates on fixed (curvature controlled) balls. These coordinates possess better regularity properties than Riemannian normal coordinates.

Journal ArticleDOI
TL;DR: In this paper, the authors applied a large AO basis to the HCl spectrum and showed that the observed deviations from the normal pattern of Rydberg states expected for a saturated system such as HCl are caused by series of curve crossings between its diffuse states and the valence σ → σ* species leading to among other things a distinctive double minimum in the 2 1 Σ + potential curve of this molecule, not suspected in earlier empirical studies of this spectrum.


Journal ArticleDOI
TL;DR: Metabolism to phenolic conjugates mainly after oral ingestion, and tom-hydroxymandelic acid after i.v. injection, again demonstrated thatm-Hydroxylated amines are predominantly conjugated during the “first-pass” metabolism.
Abstract: 7-3H-phenylephrine was given to 15 volunteers by a short-infusionn=4) or p.o. (10 volunteers, 1 patient with porto-caval anastomosis). Analysis of serum for free3H-phenylephrine and fractionation of urinary radioactivity was performed by ion-exchange and thin-layer chromatography. As almost the same3H-activity was excreted in urine after i.v. and p.o. administration, 86% and 80% of the dose respectively, complete enteral absorption can be assumed. A considerable difference was seen in the fraction of free phenylephrine, i.v. 16% of the dose versus p.o. 2.6%, which suggested reduced bioavailability. This was confirmed by comparison of the areas under the serum curve, which showed a bioavailability factor of 0.38. The result for the patient with porto-caval anastomosis was comparable to that in the normal volunteers. The biological half-life of 2 to 3h was comparable to that of structurally related amines, as were the total clearance of 2 1/h, and the volume of distribution of 340l. Metabolism to phenolic conjugates mainly after oral ingestion, and tom-hydroxymandelic acid after i.v. injection, again demonstrated thatm-hydroxylated amines are predominantly conjugated during the “first-pass” metabolism.

Journal ArticleDOI
TL;DR: In this paper, it was shown that the existence of a closed geodesic without flat half plane has a strong effect on the geometry and topology of a Riemannian manifold of non-positive curvature.
Abstract: Let M be a complete C ~~ Riemannian manifold of non-positive sectional curvature. We say that a geodesic 9: IR~ M bounds a fiat strip of width c > 0 (a fiat half plane) if there is a totally geodesic, isometric immersion i: [0, c) x IR~M(i: [0, oo) x IR~M) such that i(0, t) = 9(0. A 9eodesic without fiat strip (without fiat half plane) is a geodesic, which does not bound a flat strip (a flat half plane). We will prove that the existence of a closed geodesic without flat half plane has rather strong consequences for the geometry and topology of M. In fact, many of the properties of a manifold of strictly negative curvature (resp. of a visibility manifold) still remain true if one assumes only the existence of a closed geodesic without flat half plane. We will discuss the existence of free (non-Abelian) subgroups of gl(M), the existence of infinitely many closed geodesics, the density of closed geodesics, and a transitivity property of the geodesic flow. It is, therefore, interesting to give conditions which ensure the existence of a closed geodesic without flat half plane. We will prove that M has a closed geodesic without flat half plane if vol(M)< oo and if M contains a geodesic without flat half plane. Note that a geodesic is not boundary of a flat strip (and a fortiori not boundary of a flat half plane) if it passes through a point p e M such that the sectional curvature of all tangent planes at p is negative. In the proofs of our results we investigate the action of rtl(M ) as group of isometries on the universal covering space H of M. In the proofs of many of our results we do not use the fact that this action is properly discontinuous and free. We, therefore, formulate these results for arbitrary groups D of isometries of H. The paper is organized as follows: In Sect. 1 we fix some definitions and notations and quote some standard results of non-positive curvature. Section 2 is the central section of this paper. We investigate the properties of those isometries of H which correspond to closed geodesics in M. We also prove

Journal ArticleDOI
TL;DR: Evaluation of follow-up examinations may most successfully be done by densitometric planimetry, which, in case of following-up studies on opacified lenses, is superior to the usual measurements of densitometer height.
Abstract: Scheimpflug photography of the anterior eye segment with densitometric image analysis to measure lens transparency has proven its value in long-term follow-up studies of lens changes. The necessary technical conditions of the SL 45 Topcon camera guarantee high reproducibility. The technical control with respect to quality in case of repeated photography is ensured by an internal standard, the camera being equipped with a five-step scale of known density values. External standardization is done by taking the densitometer height of the cornea as standard. The coefficients of variation for internal and external standards were nearly equal (∼ 5%) over the 9-month period of observation of 100 patients (3,200 photos). The coefficients of variation correspond to the standard error found with repeated lens photos of volunteers' eyes evaluated by analysis of variance of the respective data sets. The standard error for distance measurements on the x-axis (cornea thickness, depth of anterior chamber, lens thickness, etc.) is less than 3%. Evaluation of follow-up examinations may most successfully be done by densitometric planimetry, which, in case of follow-up studies on opacified lenses, is superior to the usual measurements of densitometer height. The light scatter registered by Scheimpflug photography is highly individual. This is demonstrated by densitograms of normal lenses of persons of different age groups. Besides linear densitometry, various other procedures of densitometric planimetry are possible. The best results so far were obtained by multilinear densitometry, but the enormous amount of data obtained in this way renders routine application rather difficult.

Journal ArticleDOI
TL;DR: The IHI system has four vibrationally bonded collinear bound states, which are located in the saddle point region of a minimum-free potential energy surface as mentioned in this paper, which is the same region of the IHI saddle point.

Journal ArticleDOI
TL;DR: The application of stable isotope labelled drugs in clinical pharmacokinetic studies has rapidly increased over the past decade and the major advantages are that time-dependent variations in drug disposition are minimised; a small number of subjects are required in bioavailability studies; and patients are less inconvenienced.
Abstract: The application of stable isotope labelled drugs in clinical pharmacokinetic studies has rapidly increased over the past decade. Isotopes are atoms of the same chemical element, but differ from one another by their mass, due to the different number of neutrons in the nucleus. As they are not radioactive they can be administered in therapeutic doses to man. The major applications of stable isotope labelled drugs are as an internal standard in gas chromatography-mass spectrometry (GC-MS) analysis and as so-called ‘biological internal standards’. This latter application is accomplished by administering the stable isotope labelled drug to man, measuring its plasma concentration and determining various pharmacokinetic parameters. Problems associated with this technique include having a suitable mass difference between labelled and unlabelled drug, having the label in the fragment ion to be monitored and exclusion of isotope effects. The applications of the technique include investigations into the pharmacokinetics and autoinduction of carbamazepine metabolism in epileptic patients during long term monotherapy and combination therapy, and determination of the time course of carbamazepine disposition in children, studies of valproic acid pharmacokinetics during combined anticonvulsant therapy and during pregnancy, and the influence of valproic acid on phenobar-bitone (phenobarbital) disposition. These studies have been conducted in patients by substituting the normal dose with a pulse dose of the labelled antiepileptic drug and hence normal therapy was continued and not withdrawn. Also, several studies have been conducted with a solution of stable labelled verapamil, including single dose and multiple dose pharmacokinetics, and disposition and bioavailability in liver cirrhosis and in a patient before and after construction of a mesocaval shunt. Aspects of drug metabolism have also been studied by the use of stable isotopes. These include the metabolism of procainamide and N-acetylprocainamide. Stereoselectivity of drug metabolism has been investigated using a pseudoracemate of warfarin, and the interaction of the enantiomers of warfarin with phenylbutazone and with quinalbarbitone (secobarbital) has elegantly demonstrated this stereoselectivity of human drug metabolism. Absolute bioavailability studies with N-acetylprocainamide, barbitone and verapamil have been performed with stable isotopes in that both the intravenous and oral doses were given simultaneously to man. The advantage of this technique has been clearly demonstrated in a study on the relative bioavailability of 2 different Imipramine formulations, in which it was shown that to detect a 20% difference in area under the plasma concentration-time curve (with a probability of 0.8) between the 2 formulations required the use of 20 subjects, but only 3 to 4 subjects with the stable isotope method. Other studies on the relative bioavailability of different formulations have been conducted with maprotiline, verapamil and timolol. The influence of formulation factors on the absorption of benoxaprofen, dextropropoxyphene and methoxsalen have been conducted by using solutions of their stable isotopes. The major advantages of using stable isotope labelled drugs are: (a) that time-dependent (i.e. day-to-day) variations in drug disposition are minimised; (b) a small number of subjects are required in bioavailability studies; and (c) patients are less inconvenienced, for studies which normally require dosing on 2 occasions can now be easily accomplished on the 1 occasion.

Journal ArticleDOI
TL;DR: While female sexual differentiation is characterized by failure of the dark mesonephric cells to completely penetrate the gonadal blastema, the morphogenetic process resulting in the formation of the ovarian cortex shows a strong invasion of the cortex by the dark somatic cells.
Abstract: The morphogenesis of the primary gonadal differentiation, of the sexual differentiation and the growth of the ovarian cortex during its early period have been studied on 10 human embryos between 12 and 95 mm CR-length. Semithin sections of glutaraldehyde-OsO4-fixed and plastic-embedded material were used to demonstrate the structural events on a cellular level. The primary gonadal blastema within the genital ridge is formed by two types of somatic cells: cells segregated from the mesonephros and cells of the proliferating coelomic epithelium. The two types of cells show a tendency to intermingle and they enclose the immigrating primordial germ cells. In the female gonad the indifferent period terminates between day 40 and 42 of ovulation age (20 to 23 mm CR-length). Between day 40 and 50 the blastemal content of the indifferent gonad is remodelled and an ovarian cortex differentiates. Cellular strands extending from the primary blastema and strands from the superficial blastemal layer contribute to the formation of the cortex. Within the newly formed medulla, remnants of the disintegrating primary blastema differentiate into medullary cords.

Journal ArticleDOI
TL;DR: In this paper, the pseudorapidity distribution of photons produced in pp interactions at s =540 GeV has been measured and compared with that of charged particles, and the correlation between photon and charged particle production has been studied.

Journal ArticleDOI
TL;DR: In this paper, potential curves have been calculated for ground and excited states of the O2 + ion employing MRD-CI treatment in a series of AO basis sets including one of a double-zeta plus polarization quality.
Abstract: Potential curves have been calculated for ground and excited states of the O2 + ion employing MRD-CI treatment in a series of AO basis sets including one of a double-zeta plus polarization quality. Over-all good agreement is obtained for structural parameters of the various states as well as for vertical and adiabatic transition energies; the D e value for the 2Π g ground state is obtained as 6·20 eV in the best treatment (using bond functions), compared to the experimental value of 6·78 eV. The crossing of the various potential curves are described very well in the theoretical treatment with the b 4Σ g - species being intersected by the 4Σ g + and f 4Π g curves at υ = 4–5 and υ = 6–7, as compared to experimental inferences based on observed predissociation onsets of υ = 4 (N = 9) and υ = 7 respectively. Spin-orbit coupling matrix elements for both one- and two-electron interactions have been computed using the large-scale CI wavefunctions. The calculated X 2Π g spin-orbit coupling constants agree with th...

Journal ArticleDOI
TL;DR: In this paper, the second-order interference of pion pairs of equal charge is observed in good statistics samples of 16 GeV/c π+p and K−p interactions (2 × 106 and 106 pion pair combinations, respectively) and in a smaller sample of p p annihilations at rest.