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  • 1985-1989
  • 1975-1979  (2,766)
  • 1978  (2,766)
  • Polymer and Materials Science  (2,653)
  • Rat
  • pharmacokinetics
Material
Years
  • 1985-1989
  • 1975-1979  (2,766)
Year
  • 1
    Electronic Resource
    Electronic Resource
    Springer
    Experimental brain research 31 (1978), S. 433-443 
    ISSN: 1432-1106
    Keywords: Rat ; Soleus ; Fusimotor innervation ; Skeletofusimotor innervation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary In the small segmental tail muscles of the rat beta fibres provide exclusively the dynamic fusimotor control, while gamma fibres provide exclusively the static fusimor control. The present experiments were made to investigate the fusimotor innervation of spindles in a large muscle of the rat, the soleus, and thus to determine the occurrence and significance of beta innervation in this muscle. Our results have revealed no case of beta innervation in the rat soleus. As a consequence of our experimental method, however, we would not claim that beta innervation does not exist in the soleus, only that it must play an insignificant role relative to that seen in the tail segmental muscles. Investigations of the fusimotor innervation of eight spindles were sufficiently complete to warrant detailed illustration. The number of gamma fibres ranged from two to four. In every case the slowest conducting gamma fibre was dynamic. However, the conduction velocity spectra for the static and dynamic gamma fibres to rat soleus overlap to such an extent that it is impossible to use conduction velocity as the sole guide to functional gamma fibre classification. The pooled results from the eight spindles fully investigated provide a ratio of static to dynamic gamma fibres of approximately 1:1. Other evidence discussed in the paper suggests that in the muscle nerve the ratio is considerably higher. These differences are reconciled if the dynamic gamma fibres branch more profusely and innervate more spindles than do the static gamma fibres.
    Type of Medium: Electronic Resource
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  • 2
    Electronic Resource
    Electronic Resource
    Springer
    Experimental brain research 31 (1978), S. 573-590 
    ISSN: 1432-1106
    Keywords: Hippocampus ; Place units ; Unit recording ; Sensory cues ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Place units in the dorsal hippocampus of the freely-moving rat signal the animal's position in an environment (place field). In the present experiments, thirty four place units were recorded in two different environments: one, a small platform where the rat had received neither training nor reward; the other, an elevated T-maze inside a set of black curtains where the rat had been trained on a place discrimination. The places within the curtained enclosure were specified by four cues (a light, a card, a fan, and a buzzer) in addition to the food. Other cues were eliminated by rotating the maze and the four controlled cues relative to the external world from trial-to-trial. Some units had place fields in both environments while others only had a place field in one. No relationship could be seen between the place fields of units with fields in both environments. All twelve units tested extensively in the controlled enclosure had place fields related to the controlled cues. Probe experiments in which only some of the controlled cues were available showed that some of these units were being excited by one or two cues while others were influenced in a more complex way. The fields of these latter units were maintained by any two of the 4 cues and were due to inhibitory influences which suppressed the unit firing over the rest of the maze.
    Type of Medium: Electronic Resource
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  • 3
    Electronic Resource
    Electronic Resource
    Springer
    Experimental brain research 32 (1978), S. 365-375 
    ISSN: 1432-1106
    Keywords: Intraspecific aggression ; Lateral hypothalamus ; Electrical stimulation ; Specificity ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The effects of electrical stimulation of the lateral hypothalamus (LH) of rats on intraspecific aggressive behaviour were studied. In order to investigate the specificity of the stimulation effects, each experimental animal was stimulated in a number of different social situations. Stimulation of the LH in the presence of a subordinate male increased the amount of time spent on aggressive behaviour patterns and locomotion. In the presence of a dominant male, however, the stimulated animal never initiated a fight, whereas in the presence of an estrous female attack occurred in some rare occasions and sexual behaviour disappeared almost entirely. Stimulation of some sites also elicited mouse killing behaviour. Many of the electrodes that elicited intraspecific aggressive behaviour also supported intracranial self-stimulation. It is concluded that 1. electrical stimulation of this area of the LH predominantly potentiates intraspecific aggressive behaviour, 2. that this behaviour becomes overt depends on the external situation, including the behaviour of the opponent.
    Type of Medium: Electronic Resource
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  • 4
    Electronic Resource
    Electronic Resource
    Springer
    Experimental brain research 33 (1978), S. 213-225 
    ISSN: 1432-1106
    Keywords: Rat ; Hypoglossal nucleus ; Axotomy ; ATP-ase
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The hypoglossal nuclei of adult male albino rats, either normal, or from 1 to 70 days after left hypoglossal nerve transection, were studied cytochemically with a lead method for sodium- and potassium-activated membrane ATP-ase, using light and electron microscopy. Reaction product was measured at the light microscopical level by microdensitometry, and significance determined statistically. Light microscopy revealed a brown reaction product in the neuropil, but none in cell bodies. Blood vessel walls were more strongly coloured. Reaction product was undiminished by ouabain pre-incubation, or by incubation without sodium or potassium, or by incubation with calcium instead of magnesium. Reaction product was diminished by absence of magnesium if calcium was also absent, and abolished if sections were boiled before incubation, or if substrate was absent. Axotomy caused a statistically significant increase in neuropil reaction product in injured nuclei, maximal at 35 days postoperatively, and subsequently decreasing to normal at 70 days. Electron microscopy showed a predominantly surface membrane reaction product, with occasional positive intracellular cisternae. Basal lamina and intra-endothelial vacuoles were also positive. Axotomy resulted in the arrival and disappearance of microglia (2 to 35 days), followed by astrocyte hypertrophy (35 days), and increase in thickness and homogeneity of surface membrane reaction product. The results suggest the presence of one or more calcium- or magnesium-dependent membrane ATP-ases. The peak of the increase after axotomy is probably partly attributable to hypertrophic astrocytes, and partly to the surfaces of neuronal processes. Increase of membrane movements might explain such enzyme activity.
    Type of Medium: Electronic Resource
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  • 5
    Electronic Resource
    Electronic Resource
    Springer
    Psychopharmacology 56 (1978), S. 211-215 
    ISSN: 1432-2072
    Keywords: Chlordiazepoxide ; d-Amphetamine ; Response force ; Punishment ; Stereotyped behavior ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Rats were reinforced with water on a continuous reinforcement schedule and were also punished with electric shock for every fifth response applied to a silent, isometric, force-sensing manipulandum. Oral doses of chlordiazepoxide (3.0, 9.0, 27.0 mg/kg) increased both conventional rate and force of punished responding. In contrast, d-amphetamine (0.8, 1.6, 3.2 mg/kg, by gavage) further decreased conventional rate and force of response, but this latter drug increased the rate of recorded responses that were lower than the 15-g force criterion for response consequences. The results for chlordiazepoxide are viewed in terms of its anxiolytic properties, while the d-amphetamine data appear to support a theory of amphetamine effects based on the concept of stereotyped behaviors.
    Type of Medium: Electronic Resource
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  • 6
    ISSN: 1432-2072
    Keywords: Ethanol ; Tolerance ; Behavioral augmentation ; Physical dependence ; Carry-over ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Adult male rats were subjected to 1–4 cycles of daily gastric intubation with ethanol (6 g/kg) for 16 days, separated by 17-day alcohol-free periods. Tolerance produced by this treatment (designated ‘physiological tolerance’) was measured by change in effect of a 2.2 g/kg i.p. dose of ethanol on the moving-belt test. It occurred in each cycle, disappeared completely in the drug-free periods, and developed more rapidly in the second and later cycles than in the first. Tolerance produced by the ‘behavioral augmentation’ technique (daily test practice under the influence of ethanol) also developed more rapidly on a second than on a first cycle. The progression from within-session to between-session tolerance was still evident, but accelerated. With 25-day alcohol cycles, separated by a one-month drug-free period, the ‘carry-over’ effect (i.e., more rapid acquisition of tolerance in the second cycle) applied equally, regardless of whether or not tolerance was produced by the same technique in both cycles, or by a crossover in either direction between the two techniques.
    Type of Medium: Electronic Resource
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  • 7
    ISSN: 1432-2072
    Keywords: Polyphloretin phosphate ; Prostaglandins ; Behaviour ; Temperature ; Bram biogenic amines ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The possibility that polyphloretin phosphate (PPP) antagonizes the central effects elicited by prostaglandin (PG) E2 and F2α was investigated. PPP was administered i.c.v. to male Wistar rats (10 or 25 μg) 10 or 30 min before i.c.v. injection of PGE2 or PGF2α (1 or 10 μg). The duration of several components of behavior, the degree of irritability, and the rectal temperature of rats were measured; the levels of noradrenaline, dopamine, 5-hydroxytryptamine, and 5-hydroxyindoleacetic acid were measured spectrophotofluorometrically in discrete brain areas. PPP antagonized temperature and behavioral changes induced in rats by PGF2α, but not those induced by PGE2. The magnitude of antagonism depended on the dose of PPP and on the time of the pretreatment before PGF2α administration. Changes in the level of biogenic amines in discrete brain areas evoked by PGs were not affected by PPP. We found that PPP antagonizes the central effects of PGF2α but not those of PGE2, and that changes of biogenic amines in discrete brain areas elicited by PGs are not specific.
    Type of Medium: Electronic Resource
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  • 8
    Electronic Resource
    Electronic Resource
    Springer
    Virchows Archiv 378 (1978), S. 45-53 
    ISSN: 1432-2307
    Keywords: Alcohol ; Myopathy ; Histochemistry ; Electrophysiology ; Human ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Muscles of the lower legs of rats given 25% ethanol in water ad libitum for up to 9.5 months were studied using histological, histochemical and electrophysiological techniques. Ethyl alcohol was substituted for about 20% of the total calorific input of the animals. The observations were compared with the structure of the gastrocnemius muscle of five alcoholics with clinical neuropathy. Fibrillation potentials and angulated atrophic fibers were observed in the muscles of animals on alcohol for 9.5 months. No fiber type grouping was present. There was also phagocytosis of the muscle fibers and changes in their internal structure, as reflected by the distribution of NADH-diaphorase. The observed muscle changes in the alcoholics and those in the experimental animals on alcohol differed mainly quantitatively, the only exception being the presence of fiber type grouping in the biopsies from the alcoholics.
    Type of Medium: Electronic Resource
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  • 9
    Electronic Resource
    Electronic Resource
    Springer
    Research in experimental medicine 173 (1978), S. 239-244 
    ISSN: 1433-8580
    Keywords: Experimental chronic uremia ; Rat ; Oxygen consumption ; Body weight ; Experimentelle chronische Urämie ; Ratte ; Sauerstoffverbrauch ; Körpergewicht
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Zusammenfassung Die verminderte Gewichtszunahme bei experimenteller chronischer Urämie führte zu der Bestimmung des Sauerstoffverbrauches chronisch urämischer Ratten und eines normalen Vergleichskollektivs. Die Messung des Sauerstoffverbrauches wird als Hinweis auf den Energiebedarf des Gesamtstoffwechsels gewertet. Drei Gruppen von Versuchstieren wurden untersucht: urämische Ratten (CU) von geringerem Gewicht (403,66 ± 9,9 g) als deren gesunde Vergleichstiere (NA) (498,31 ± 26,13) und jüngere Normaltiere (NJ), welche ein annähernd ähnliches Körpergewicht wie die chronisch Niereninsuffizienten aufwiesen (376,0 ± 8,8). Signifikante Unterschiede des Sauerstoffverbrauches, bezogen auf das Körpergewicht, wurden zwischen den Gruppen NJ (0,927 ± 0,042 ml O2/mn/100 g Ratte) und beiden Gruppen CU und NA (0,788 ± 0,036 und 0,788 ± 0,028 jeweils) gefunden. Eine proportionale Verminderung der energetisch aktiven Körpermasse mag die Ursache der Sauerstoff-Meßergebnisse bei chronischer experimenteller Urämie sein.
    Notes: Summary Impaired weight gain, a common feature in experimental chronic uremia, led to compare oxygen consumption values of chronic uremic rats and their controls. Oxygen consumption measurement may allow an approach to the evaluation of total energy requirement. Three groups of animals were considered: uremic rats (CU) of less weight (402.66 ± 9.9 g) than their control group (NA) (498.31 ± 26.13) and younger normal animals (NJ), showing a similar weight (376.0 ± 8.8) to that of the uremics. Significant differences in oxygen consumption values/body weight were found between group NJ (0.927 ± 0.042 ml O2/mn/100 g rat) and both groups CU and NA (0.788 ± 0.036 and 0.788 ± 0.028 respectively). Proportional decrease of energetically active body mass in chronic uremic animals may be the reason of the findings.
    Type of Medium: Electronic Resource
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  • 10
    Electronic Resource
    Electronic Resource
    Springer
    Research in experimental medicine 174 (1978), S. 57-65 
    ISSN: 1433-8580
    Keywords: Complement system ; Sodium taurocholate ; Acute experimental pancreatitis ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The role of the complement system was studied in Na-taurocholate pancreatitis in rats. Complement activity (CH 50) was determined at various times in the course of pancreatitis. Immediately after induction of acute pancreatitis, serum complement activity declined and massive C 3 deposits could be detected in the vicinity of acinar necroses and necrobioses. After a phase of recovery three to six hours postoperatively a second complement consumption occurred. Lethality rate increased as serum complement activity fell below 50% of preoperative values. The degree of C 3 deposition increased up to six hours. Decline of serum complement activity and deposition within the pancreas seemed to be correlated with histologically demonstrable tissue lesion. The first decline of complement activity in serum is thought to be caused by liberation of complement activating substances within the pancreas due to the detergent action of Na-taurocholate itself. The second decline, however, may be due to the liberation of complement activating and/or destroying enzymes into the blood stream.
    Type of Medium: Electronic Resource
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  • 11
    Electronic Resource
    Electronic Resource
    Springer
    Research in experimental medicine 172 (1978), S. 247-253 
    ISSN: 1433-8580
    Keywords: Rat ; Parotid saliva
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary A method is described, which is suitable to collect continuously and quantitatively saliva from both parotid glands in rats under in vivo conditions and which allows to investigate salivary electrolyte composition in relation to flow rate during several hours. This might be of expanding scientific interest in disturbances of transepithelial electrolyte transport in various pathophysiological situations (for instance different forms of experimental hypertension, endstage renal failure and so on).
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  • 12
    Electronic Resource
    Electronic Resource
    Springer
    Anatomy and embryology 154 (1978), S. 27-37 
    ISSN: 1432-0568
    Keywords: Capillarization ; Cortex ; Rat ; 6-Aminonicotinamide
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary During different embryonic and postnatal stages, 6-aminonicotinamide (6-AN) was administered to Wistar albino rats. The capillarization of the occipital cortex has been examined morphometrically. A 6-AN-vulnerable stage of prenatal development was found, which lasted to the 19th prenatal day and which only partly corresponds to the so-called ‘critical stage’ of capillary sprouting (Kapillarsprossung). Capillary sprouting was not impaired by 6-AN during postnatal stages. Impairment of capillarization by 6-AN might be the result of glial lesion. The importance of glia for capillarization is discussed.
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  • 13
    Electronic Resource
    Electronic Resource
    Springer
    Anatomy and embryology 153 (1978), S. 1-8 
    ISSN: 1432-0568
    Keywords: Ileal epithelial cell ; Suckling period ; Rat ; Scanning electron microscopy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The ileal epithelial cells containing the tubulo-vacuolar systems and supranuclear vacuoles in suckling rats were investigated with scanning electron microscopy, using specimens treated with osmium-thiocarbohydrazide-osmium staining methods, and critical point drying and cracking. The cracked surface of the apical cytoplasm is seen as irregular and small hollows and pores of the anastomosing and branching tubulo-vacuolar system. The cracked surface of the supranuclear vacuoles shows the ellipsoidal structures. Numerous pores of various size and irregular shape are present on the apical inner surface of the supranuclear vacuole. These pores are clearly the openings from the tubulo-vacuolar system to the supranuclear vacuole. Some small pores are visible on the inner lateral surface of the supranuclear vacuole, especially near the nucleus. They are probably the pathways of the absorbed materials from the supranuclear vacuole into the lateral cytoplasm. Usually, the inclusions of the supranuclear vacuole reveal the globes or coarse and sponge-like networks.
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  • 14
    ISSN: 1432-0568
    Keywords: Rat ; Iris ; Cornea ; Catecholamine fluorescence ; Cholinesterase ; Histochemistry ; Ontogenesis ; Catecholamines
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Glyoxylic acid-induced fluorescence technique and a copper thiocholine method were used to investigate the ontogenesis of the catecholamine-containing and cholinesterase-positive nerves of the rat iris and cornea. First fluorescent nerve fibres appeared in the iris on the 18th gestation day and in the cornea on the 19th day. A rapid increase in the density of the adrenergic nerve fibres of the iris continued to the age of three weeks, while the number of such fibres were small in the cornea. Acetylcholinesterase-positive fibres appeared both in the cornea and in the iris on the 19th gestation day. Their density increased more rapidly in the iris, especially in the sphincter muscle, than in the cornea. Non-specific cholinesterase activity was localized in the Schwann cells and the reaction was more intense during development than in the nerves of the cornea of adult rats.
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  • 15
    Electronic Resource
    Electronic Resource
    Springer
    Anatomy and embryology 154 (1978), S. 241-251 
    ISSN: 1432-0568
    Keywords: Nervous system ; Serotonin ; Raphe nuclei ; Development ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The pre- and early postnatal development of serotonin neurons in the rat brainstem was studied using the fluorescence histochemical method. The technique utilized does not require drug pretreatment to visualize an intense serotonin fluorophore localized in neuronal perikarya, dendrites, and axons. All the serotonin neuron groups develop as bilateral nuclei which extend from the midbrain through the medulla. Six of the nine groups undergo a midline fusion from embryonic day 18 (E 18) through postnatal day 6 (P 6) in a rostrocaudal gradient. Cells of the nucleus raphe dorsalis fuse first (by P1), whereas the serotonin neurons located in nucleus raphe pallidus do not fuse until P 6. This gradient is comparable to the one described for the first observable fluorescence in the serotonin neurons groups. After final cell division, the serotonin neurons undergo a primary migration from the ventricular zone along the midline, where they are situated during embryogenesis, and a secondary migration extending into postnatal life which concludes with fusion in the midline. The bilateral origins of the serotonin cell groups are maintained in the adult. This is expressed by the apparent ipsilateral projections of some of the raphe neurons determined recently in our laboratory utilizing autoradiographic and horseradish peroxidase techniques.
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  • 16
    Electronic Resource
    Electronic Resource
    Springer
    Annals of hematology 37 (1978), S. 295-306 
    ISSN: 1432-0584
    Keywords: Β-adrenerge Rezeptoren ; (3H) (−) Dihydroalprenolol ; Erythrozyten ; Ratte ; Β-Adrenoceptors ; (3H) (−) Dihydroalprenolol ; Erythrocytes ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Summary By means of the radioactive antagonist ligand (3H) (−) dihydroalprenolol (DHAP) specific binding sites were identified in membrane preparations from red blood cells from rats. These specific sites were characterized asΒ-adrenoceptors because of the following reasons: Specific binding of DHAP (in contrast to unspecific binding) was dependent on temparature and time of incubation. Furthermore, specific binding of DHAP showed saturability, temperature-dependent reversibility and high affinity (KD-value of DHAP = 6.51 nM). Specific binding of DHAP was competitively inhibited byΒ-adrenergic antagonists (pindolol 〉 alprenolol ≧ propranolol 〉 practolol) and agonists (isoprenaline 〉 adrenaline). The (−) enantiomers of pindolol and isoprenaline showed pronounced higher affinities for the receptor sites than the respective (+) enantiomers. The receptor density in the membrane preparations (pmoles/mg protein) was strongly dependent on the degree of reticulocytosis: The Bmax-values increased more than 4 to 5 fold without alteration of the respective KD-values when reticulocyte counts were enhanced from 3 to 80 % treatment of the animals with increasing doses of acetyl phenylhydrazine.
    Notes: Zusammenfassung Mittels des radioaktiv markierten Antagonist-Liganden (3H) (−) Dihydroalprenolol (DHAP) wurden spezifische Bindungsstellen in Membran-PrÄparationen von Erythrozyten der Ratte identifiziert, die aus folgenden Gründen alsΒ-adrenerge Rezeptoren angesprochen werden können: Im Gegensatz zur unspezifischen Bindung von DHAP war die spezifische Bindung abhÄngig von der Inkubationszeit und der Temperatur. Sie folgte einer SÄttigungskinetik, war — in AbhÄngigkeit von der Temperatur — reversibel und wies eine hohe AffinitÄt auf (KD für DHAP = 6,51 nM). Die rezeptorspezifische Bindung von DHAP wurde durchΒ-Rezeptorenblocker (Pindolol 〉 Alprenolol ≧ Propranolol 〉 Practolol) oderΒ-Sympathomimetika (Isoprenalin 〉 Adrenalin) kompetitiv gehemmt. Die (−) Enantiomeren von Pindolol und Isoprenalin hatten eine wesentlich höhere AffinitÄt als die antsprechenden (+) Enantiomeren. Die Dichte Β-adrenerger Rezeptoren (pmole/mg Eiwei\) nahm mit steigendem Retikulozytosegrad zu: Sie stieg auf das 4-bis 5fache an, wenn die Retikulozytenwerte durch Vorbehandlung der Tiere mit Azetylphenylhydrazin von 3 auf 80 % gesteigert wurden.
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  • 17
    Electronic Resource
    Electronic Resource
    Springer
    Archives of dermatological research 262 (1978), S. 167-172 
    ISSN: 1432-069X
    Keywords: Rat ; Oxygen uptake ; Induced skincycle ; Spontaneous skincycle ; Diurnal rhythm ; Ratte ; Sauerstoffverbrauch ; Induzierter Hautcyclus ; Spontaner Hautcyclus ; Tagesschwankung
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Zusammenfassung In der vom Panniculus carnosus gereinigten “glatten” Rattenhaut wurde der Sauerstoffverbrauch des spontanen und induzierten Hautcyclus zu verschiedenen Tageszeiten ermittelt. Das Niveau des Sauerstoffverbrauches korrelierte mit den Tag-Nacht-Zeiten. Der Sauerstoffverbrauch zeigte während des Hautcyclus Schwankungen. Ferner fanden sich Anhaltspunkte, daß der frühanagene Wert des Sauerstoffverbrauches von der Cyclusphase mit beeinflußt wird, während welcher der neue Cyclus künstlich induziert wird. Weiter wurde festgestellt, daß eine gewisse Abnahme des Sauerstoffverbrauches die ruhenden Haarfollikel zur spontanen Proliferation anregt. Während des Katagen schien der Maximalwert des Sauerstoffverbrauches mit speziellen morphofunktionellen perifollikulären Veränderungen in Beziehung zu stehen. Die Übertragung dieser Befunde auf die Pathophysiologie menschlicher Haarwachstumsstörungen wird erwogen.
    Notes: Summary In the “clean” rat skin purified from the panniculus carnosus the oxygen consumption of the spontaneous and artificially induced skincycle was measured at different times of day. The level of oxygen consumption correlated to diurnal and nocturnal periods. During the skincycle the oxygen consumption showed fluctuations. There were indications that the value of oxygen consumption of the early anagen is influenced by that phase of the cycle at which the new cycle is artificially induced. Furthermore, it was found that a certain decrease of oxygen consumption stimulates the quiescent hair follicles to spontaneous proliferation. During the katagen the peak value of the oxygen consumption seemed to be correlated with specially morphofunctional perifollicular changes. The application of these findings to the pathophysiology of human hair growth disturbances is discussed.
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  • 18
    Electronic Resource
    Electronic Resource
    Springer
    Acta neuropathologica 42 (1978), S. 159-164 
    ISSN: 1432-0533
    Keywords: Perhexiline maleate ; Pexid ; Abnormal inclusion ; Rat ; CNS
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The basic cellular lesion in CNS of suckling rats treated with Pexid was studied by light and electron microscopy. The most pronounced abnormality, the formation of various intracytoplasmic inclusions, was found in neurons, astrocytes, oligodendrocytes, ependymal cells, endothelial cells and fibroblasts. These abnormal inclusions were generally membrane-bound, although clearly non-membrane-bound inclusions were occasionally found. The several internal patterns of the inclusions were (1) lamellar, both concentric and parallel, (2) reticular and (3) crystalloid. These alterations were completely resersed following withdrawal of the drug. The structural characteristics of the abnormal inclusions in Pexid-treated animals were similar to those found with certain hypocholesterolemic, neuroleptic, anorectic, and antimalarial drugs. This suggests that the inclusions occurring within the cells of animals treated with any of these drugs may develop in a similar manner, and that the formation of such inclusions is likely to be a form of cellular reaction common to certain metabolic disturbances.
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  • 19
    Electronic Resource
    Electronic Resource
    Springer
    Acta neuropathologica 44 (1978), S. 53-56 
    ISSN: 1432-0533
    Keywords: Blood-brain barrier ; Air embolism ; Horseradish peroxidase ; Cerebral cortex ; Electron microscopy ; Carotid artery ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Male albino rats were anaesthetized with diazepam, injected with horseradish peroxidase and Evans blue-labeled albumin and given an embolus of 0.01 ml air in the right common carotid artery after ligation of the external carotid branch. The pial arteries of the right cerebral hemisphere were stained blue, particularly the middle cerebral artery and its main arterial branchlets. Ultrastructurally, some endothelial cells in the right middle cerebral artery, small arteries and arterioles showed a diffuse distribution of horseradish peroxidase in their cytoplasm, although these vessels only occasionally showed peroxidase in their basement membranes. Other endothelial cells in these arterial branchlets showed few if any signs of a diffuse distribution of peroxidase but displayed several pinocytotic vesicles and occasionally trans-endothelial channels filled with peroxidase, sometimes with a slight leakage of peroxidase into adjacent basement membranes and neuropil. Scattered pinocytotic vesicles were observed in capillaries and venules, but there was usually no extravasation of peroxidase around these vessels.
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  • 20
    Electronic Resource
    Electronic Resource
    Springer
    Acta neuropathologica 44 (1978), S. 147-149 
    ISSN: 1432-0533
    Keywords: Cadmium ; Endothelial cell ; Capillary ; Fetal brain ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Pregnant rats received a single administration of 0.5, 1.0, or 2.0 mg/kg of cadmium on day 18 or 20 or gestation Maternal animals were killed on day 21 and samples of the caudate nucleus from fetal brains were examined using the transmission electron microscope. A 2.0 mg/kg dose of cadmium administered to maternal rats on day 20 of gestation caused the formation of vacuoles in the endothelial cells of capilaries in the fetal brain. Significant endothelial cell vacuolization was not observed in the brain of fetuses from other treatment groups. The vacuoles occurred singly, were spherical in shape, were located adjacent to the intercellular junctions and caused focal distortion of the endothelial cell. Vacuoles were the only ultrastructural alteration observed in the caudate nucleus of fetal brains.
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  • 21
    ISSN: 1432-0533
    Keywords: Protein-calorie malnutrition ; Rat ; Spinal root ; Sciatic nerve ; Internodal length
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The current investigation comprised normal young rats as well as rats submitted to a 50% food reduction or severe protein restriction. Isolated nerve fibres from lumbar spinal roots and sciatic nerves were investigated with reference to the relation between length and diameter of internodes as well as variation of internodal length along single nerve fibres. The present results do not support the view that protein-calorie malnutrition should cause neuropathy. Internodal segments were, on an average, shorter in relation to their thickness in young rats submitted to severe protein restriction or a 50% food reduction. The deviation was most marked in low-protein animals and particularly among coarser internodal segments. An inhibition of longitudinal growth was considered to be the main factor behind the difference between malnourished and normal rats.
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  • 22
    ISSN: 1432-0533
    Keywords: Experimental brain gliomas ; Chemically induced ; Rat ; Cell cultures ; Humoral antibodies ; Immunofluorescence staining ; Microcytotoxicity assay
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Brain tumors were induced in Sprague-Dawley and Long-Evans rats by administration of N-methyl-N-nitrosourea in the drinking water. Of these tumors, a grade 2 mixed glioma, a grade 2 to 3 astrocytoma and a grade 1 to 2 oligodendroglioma were established in vitro, maintained in culture and designated 75SD-G-376, 75SD-G-420 and 77LE-G-180, respectively. Of these mass cultures, two were successfully cloned and are currently available as 75SD-G-376C and 75SD-420C cell lines. Clonal lines produce S-100 protein and grow as tumors when isografted in young rats. Using the cultured cells as target cells, specific antibodies were searched for in the sera of the rats with the primary tumors by means of an indirect fluorescent antibody staining method and a complement-dependent antibody-mediated microcytotoxicity assay. Fluorescent and cytotoxic antibodies were demonstrated in the sera of the mixed glioma- and astrocytoma-bearing animals. However, a variable proportion of cells of the 75SD-G-376 and 75SD-G-420 lines showed no reaction with the corresponding sera. Furthermore, cytotoxic anfibodies had a lytic effect on the autologous glioma cells only in the presence of rabbit complement.
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  • 23
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    Acta neuropathologica 44 (1978), S. 245-247 
    ISSN: 1432-0533
    Keywords: Schwann cells ; PNS myelin ; Retina ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Within the retinal nerve fiber layer of a 6-week-old Sprague-Dawley rat, scattered aggregates of PNS myelinated axons have been found and described. We believe this is likely to represent a normal but rare phenomenon in the rat.
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  • 24
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    Calcified tissue international 25 (1978), S. 75-83 
    ISSN: 1432-0827
    Keywords: Rat ; Fluorosis ; Enamel ; Scanning electron microscopy ; Low temperature incineration
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine , Physics
    Notes: Summary Sixteen 58-day-old male rats of Wistar strain, with a mean body weight of 179 g, were divided into two equal groups. Each group of eight animals was maintained for 70 days on drinking water, ad lib., containing no fluorine (control group) and 100 ppm of fluorine (experimental group). All specimens examined were obtained from the incisal portions of the incisors. The following types of enamel specimens were prepared for scanning electron microscopy: (1) acid-etched specimens; (2) acid-etched specimens followed by low temperature microincineration; and (3) fractured specimens. The enamel formed during high fluoride exposure showed marked hypocalcification, that is, the crystallite density in the prism core and interprismatic region was lower than that of control animals. The organic substances appeared to increase in these regions. These changes were prominent in the outer and middle enamel layers. Such changes following fluoride administration appear to indicate an inhibition of enamel maturation, that is, an inhibition of the mineral deposition and/or an inhibition of organic matrix withdrawal.
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  • 25
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    Naunyn-Schmiedeberg's archives of pharmacology 303 (1978), S. 165-170 
    ISSN: 1432-1912
    Keywords: Striatum ; Evoked potentials ; Neuroleptics ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The interaction of cortico- and nigrofugal inputs to the striatum of the rat was investigated using the technique of evoked potentials. Repetitive, unilateral stimulation of the substantia nigra inhibited potentials which were evoked from the ipsilateral rostral cortex and recorded from the ipsilateral striatum. The inhibition was antagonized by low doses of various intraperitoneally administered neuroleptics such as: pimozide (0.1–0.2 mg/kg), haloperidol (0.1–0.5 mg/kg), chlorpromazine (0.5–2.0 mg/kg) and thioridazine azine (0.5–4.0 mg/kg). These findings are discussed in view of the existing controversy regarding the mode of action of dopamine in the striatum.
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  • 26
    ISSN: 1432-2013
    Keywords: Oxygen dissociation curve ; Oxygen transport ; Cardiac output ; Coronary blood flow ; Blood flow to organs ; Hypoxia ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract A major displacement of the blood O2 dissociation curve (ODC) was achieved in rats by chronic administration of sodium cyanate (NaOCN). Control animals with a normal position of the ODC received NaCl instead. Arterial and mixed-venous O2 content ( $${\text{C}}_{{\text{O}}_{\text{2}} }$$ ) and O2 consumption were measured during breathing room air, 14.9, 8.0, or 5.6% O2 in N2. Cardiac output was obtained by the Fick principle.86RbCl was administered i.v., the rats were killed and the activity of86Rb in heart, spleen, stomach and intestines, liver, kidney, skeletal muscle, and skin was measured. According to Sapirstein (1956, 1958) the fractional uptake of86Rb in these organs corresponds to the fractions of cardiac output supplying these organs, and from the fractional uptake and cardiac output the nutritional blood flow may be calculated. Arterial and mixed-venous $${\text{C}}_{{\text{O}}_{\text{2}} }$$ was larger in the NaOCN than in the NaCl rats at all levels of oxygenation. At normoxia and 14.9% O2 the venous $${\text{C}}_{{\text{O}}_{\text{2}} }$$ was enlarged more than the arterial one, and so the arterio-venous O2 difference [ $$\left( {{\text{a}} - {\text{v}}} \right)_{{\text{O}}_{\text{2}} }$$ ] as an index of the O2 extraction in the body was smaller in the rats with a left-shifted ODC. However, at more severe hypoxia (8.0 and 5.6% O2) the arterial $${\text{C}}_{{\text{O}}_{\text{2}} }$$ in the NaOCN rats was enlarged more than the mixed-venous one, resulting in a larger $$\left( {{\text{a}} - {\text{v}}} \right)_{{\text{O}}_{\text{2}} }$$ (and therefore O2 extraction) when compared with the NaCl animals. Cardiac output was larger in the NaOCN than in the NaCl rats at 14.9 and 5.6% O2, when expressed per kg body weight. At 14.9% O2 the augmented cardiac output compensated for the lower O2 extraction when compared with the NaCl animals. At 5.6% O2 the NaOCN rats had both a larger ( $$\left( {{\text{a}} - {\text{v}}} \right)_{{\text{O}}_{\text{2}} }$$ ) and cardiac output than the NaCl animals. In the NaCl rats the decreased O2 extraction was not compensated for by an augmented cardiac output and therefore their O2 consumption was not only lower than that of the NaOCN rats but decreased even below the normoxic value of the NaCl rats. Coronary blood flow was increased in both NaOCN and NaCl animals at deep hypoxia to about the same extent, but due to a much lower arterial $${\text{C}}_{{\text{O}}_{\text{2}} }$$ of the NaCl animals, their O2 supply to the heart was lower than that of the NaOCN rats. The nutritional blood flow to spleen, kidney, liver, stomach and intestines, and skin in ml/min · g was lower in the rats with a normal position of the ODC than in those with a left-shifted ODC. This, together with the low arterial $${\text{C}}_{{\text{O}}_{\text{2}} }$$ of the NaCl rats, suggests a serious compromising of the O2 supply to these organs. Results of this study support the conclusion of our theoretical studies (Turek et al., 1973; Turek and Kreuzer, 1976) that a shift of the ODC to the left might be disadvantageous for the O2 transport to tissues at mild hypoxia, but advantageous at severe hypoxia.
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  • 27
    ISSN: 1432-2013
    Keywords: Blood gases ; Cardiac hypertrophy ; Intercapillary distance ; Myocardial infarction ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract In rats with a myocardial infarction due to ligation of the left coronary artery a marked right ventricular hypertrophy developed after 41/2 weeks. At this time no difference against control animals was observed in arterial $$P_{{\text{O}}_2 }$$ , $$P_{{\text{CO}}_2 }$$ , pH, ideal alveolar $$P_{{\text{O}}_2 }$$ , and alveolar-arterial O2 pressure difference, as measured in unanesthetized animals at normoxia. In histological sections of the heart stained by PAS reaction capillaries and muscle fibers were counted, and the mean intercapillary distance and muscle fiber diameter were estimated. In the right ventricle of the rats with myocardial infarction both increased when compared with control animals or with sham-operated rats. Fibercapillary ratio was the same in all three groups. Similar results were obtained in the remaining undamaged tissue of the left ventricle of rats with a myocardial infarction when compared with the left ventricle of control or sham-operated rats. Findings concerning intercapillary distance suggest that also in the myocardium which remains intact during the development of the infarction and later hypertrophies, tissue oxygen transport might be impaired, particularly during a stress situation. Results in the right ventricle of rats with myocardial infarction show an opposite trend against rats exposed chronically to simulated high altitude, where in the hypertrophied right ventricle a shorter intercapillary distance occurs and therefore an improvement of tissue oxygen transport might be expected.
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  • 28
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    Pflügers Archiv 376 (1978), S. 245-249 
    ISSN: 1432-2013
    Keywords: Colon ; Amino acid uptake ; Basolateral membrane ; Active transport ; Sheep ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Uptake of the nonmetabolizable model amino acid 2-aminoisobutyric acid (=AIB) through the basolateral membrane into epithelial cells was studied in sheep colon stripped of serosa and muscle layers. Only the antiluminal surface of the mucosa was exposed to the incubation medium. Thus AIB entry into epithelial cells could only occur through the basolateral membrane. AIB was taken up by a saturable process against a high concentration gradient. AIB uptake was inhibited by other neutral amino acids but not by sugars. In a low Na+ medium AIB uptake was impaired, indicating that active transport of amino acids through the basolateral membrane of colon epithelial cells is Na+-dependent. In the rat a saturable concentrative uptake of AIB through the basolateral membrane of colon epithelial cells has also been demonstrated. Concentrative uptake of amino acids through the basolateral membranes is probably important for the supply of colon epithelium with amino acids.
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  • 29
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    Pflügers Archiv 373 (1978), S. 133-138 
    ISSN: 1432-2013
    Keywords: Deoxycholate ; Intestinal perfusion ; Rat ; Enzymatic release ; Localization
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The release of proteins, sucrase (SA), maltase (MA), leucine aminopeptidase (LA) and alkaline phosphatase (AP) activity from rat jejunum by sodium deoxycholate (DOC) was studied by an in vivo perfusion technique. In our experimental conditions, a 2 mmol/l DOC perfusion for 30 min induced a marked and reversible release of proteins and hydrolases. When specific activities were considered, each enzyme showed a distinct release pattern. Significantly, the SA release was largely increased, the AP release was decreased and there was no correlation between the releases of SA and AP. Furthermore, the various enzymes recovered into the lumen were solubilized at different extents. SA was chiefly present in a soluble and AP in a particular form. The microscopical appearances showed a slight exfoliation of the epithelial cells from the villous tips but no specific changes when compared to the control group. The results are discussed in terms of enzymic localization in the brush border membrane; SA would be located very superficially in the surface membrane and AP buried in the membrane and less accessible than the other enzymes.
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  • 30
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    Pflügers Archiv 374 (1978), S. 229-234 
    ISSN: 1432-2013
    Keywords: Cyclic AMP ; ADH ; Vasopressin ; Isoproterenol ; 3-isobutyl-1-methylxanthin ; Rat ; Water diuresis ; Antidiuresis ; Dehydration
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract In vivo experiments were performed in male Wistar rats to elucidate the probable relation between renal concentrating ability and medullary cyclic AMP content as influenced by changes of hydration and by administration of antidiuretic hormone (ADH). Cyclic AMP levels were 37% lower in water diuretic than in control animals (P〈0.01), but were not significantly changed during prolonged antidiuresis induced by dehydration or ADH administration. Nor could any change of cyclic AMP levels be demonstrated between 2 and 20 min after ADH injection. Significant increases of medullary cyclic AMP content occurred following stress, anesthesia, and administration of isoproterenol and 3-isobutyl-1-methylxanthin. The results suggest that the level of cyclic AMP in the renal medulla may not be an important determinant of the antidiuretic response produced by ADH in rats.
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  • 31
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    Pflügers Archiv 374 (1978), S. 285-288 
    ISSN: 1432-2013
    Keywords: High altitude ; Blood volume ; Red cell volume ; Plasma volume ; Body haematocrit ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Circulating blood volume (BV) as the sum of circulating red cell volume (RCV) and plasma volume (PV) was estimated in rats native to a simulated altitude of 3500 m (“natives”), in rats born at sea level and later in life transferred to the simulated high altitude (“newcomers”), and in control sea-level rats. RCV per kg body weight (b.w.) was significantly larger in both “newcomers” and “natives” than in controls. PV per kg b.w. was in the “newcomers” insignificantly and in the “natives” significantly smaller than in the controls. BV per kg b.w. in both high altitude groups tended to be larger than in controls but the difference was not significant. Arterial haematocrit (Ahct) in the “newcomers” was significantly higher than in the controls, and in the “natives” significantly higher than in both other groups. Body haematocrit (the ratio of RCV and BV in per cent) was smaller than Ahct in all groups; this was more pronounced in the “newcomers” than in the controls and even more so in the “natives”. Apparently the haematocrit in the minute vessels of the organs of animals exposed to chronic hypoxic hypoxia increases much less than might be expected from changes of the Ahct. An attempt was made to evaluate the possible error of the more commonly used method of estimating BV, when only RCV, or only PV, is measured, and BV and its complementary fraction are calculated from arterial or venous haematocrit. When, in our results, BV was calculated from RCV and Ahct, the absolute values and also the differences between groups were somewhat underestimated. When BV was calculated from PV and Ahct, the BV itself, and particularly the differences between groups, were overestimated quite considerably. It is suggested that the only safe way to estimate BV is to measure RCV and PV separately.
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  • 32
    ISSN: 1432-2013
    Keywords: PAH clearance ; PAH extraction ; Glomerular filtration rate ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract PAH secretion (TPAH) was studied in rats at spontaneously occurring glomerular filtration rate (GFR). At saturated transport, TPAH was found to be correlated to GFR. This relationship was also observed at unsaturated transport where TPAH depends upon the PAH concentration in arterial plasma. However, no significant correlation between TPAH and renal PAH load or renal plasma flow rate was found when the effects of GFR were removed by partial correlation analysis. A dependency of TPAH on GFR explains the correlations found between filtration fraction (FF) and renal PAH extraction (EPAH) or renal tubular PAH extraction fraction (EPAH-FFPAH). Thus, even at low PAH concentration in a. plasma, renal PAH extraction may only be assumed to be constant if the filtration fraction is constant.
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  • 33
    ISSN: 1432-2013
    Keywords: Oxygen dissociation curve ; Oxygen transport ; Blood gases ; Hypoxia ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Theoretical deductions have shown that a shift of the blood O2 dissociation curve (ODC) to the right might improve O2 transport to tissues at normoxia and at mild hypoxia whereas at severe hypoxia the organism should be better off with an ODC shifted to the left (Turek et al., 1973b; Turek and Kreuzer, 1976). The present study was performed in order to ascertain this ambiguous effect of an ODC shift depending on the degree of hypoxia in intact animals. A major displacement of the ODC to the left was achieved in rats by chronic administration of sodium cyanate (NaOCN). Control animals received sodium chloride (NaCl) instead. Arterial and mixed-venous $$P_{{\text{O}}_{\text{2}} }$$ , $$P_{{\text{CO}}_{\text{2}} }$$ , and pH were measured at normoxia and during breathing 14.9, 8.0, or 5.6% O2 in N2 in both groups. From $$P_{{\text{O}}_{\text{2}} }$$ , pH, ODC and arterial hematocrit, arterial and mixed-venous O2 contents were estimated and $$({\text{a}} - {\text{v)}}_{{\text{O}}_{\text{2}} }$$ as an index of blood O2 extraction was obtained. At normoxia and during breathing 14.9% O2 the NaOCN rats had a lower mixed-venous $$P_{{\text{O}}_{\text{2}} }$$ than the NaCl rats without any difference in pH. Arterio-venous O2 difference did not differ at normoxia but was lower in NaOCN rats at 14.9% O2. However, at 8.0 and 5.6% O2 the NaOCN rats had a higher mixed-venous $$P_{{\text{O}}_{\text{2}} }$$ , an increased $$({\text{a}} - {\text{v)}}_{{\text{O}}_{\text{2}} }$$ , and a higher pH (arterial and mixed-venous). At 5.6% O2 the NaCl rats developed a severe acidosis concomitant with pronounced hypocapnia. These findings confirm that rats with a left-shifted ODC have an impaired O2 transport to tissues at normoxia and mild hypoxia but a more efficient O2 transport at severe hypoxia as compared with rats with an unshifted ODC, in agreement with our previous theoretical studies.
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  • 34
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    European journal of clinical pharmacology 13 (1978), S. 275-284 
    ISSN: 1432-1041
    Keywords: Diazepam ; pharmacokinetics ; pregnant women ; plasma clearance ; blood/plasma concentration ratio ; placental transfer
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The disposition of diazepam has been studied in pregnant women at parturition. The plasma concentration of diazepam was monitored for at least 3 days in 18 women who received a single intravenous injection of 10 mg during the 10 h-period prior to delivery. Fourteen mothers had uneventful puerperia (Group I) and in 13 of these cases there was a pronounced postnatal increase in the plasma concentration of diazepam. The terminal phase half-life (t1/2) was significantly greater for Group I (mean = 65 h; range = 24–114 h) than for age-matched non-pregnant patients (mean = 29 h; range = 18–44 h from literature). The prolonged t1/2 appeared to be related to changes in the distribution of diazepam and not to a reduction in hepatic elimination since the total plasma clearance (Cltp) in these 14 pregnant patients (mean = 28 ml/min; range = 18–43 ml/min) was not reduced compared to that reported for non-pregnant controls (mean = 30 ml/min; range = 22–45 ml/min). Four mothers underwent postnatal surgery for tubal ligation (Group II) and the plasma concentration-time profiles for this group did not show the same postnatal phenomenon as did the profiles obtained for Group I. The t1/2 for Group II was shorter (mean = 31 h; range = 24–37 h) than for Group I and similar to that for the non-pregnant controls. The Cltp for Group II was greater (mean = 56 ml/min; range = 48–63 ml/min) than for both Group I and non-pregnant controls. These results suggest that delivery alters the disposition of diazepam and is generally associated with a postnatal re-distribution of diazepam into the systemic circulation. The blood/plasma concentration ratio was determined in 9 patients (mean = 0.62; range = 0.54–0.77). There was no difference in the total blood clearance between the pregnant patients of Group I and the non-pregnant controls. In most cases the umbilical venous plasma concentration (Cpuv) of diazepam was greater than the peripheral maternal venous plasma concentration (Cpmv) at delivery. The foetus appears to constitute a slowly equilibrating tissue-group in which diazepam does not reach equilibrium with the maternal systemic circulation for at least 5–10 h at which time the diazepam concentration in maternal and foetal plasma is similar.
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  • 35
    ISSN: 1432-1041
    Keywords: p-Chlorophenoxyisobutyric acid ; clofibrate ; steady-state plasma concentrations ; bioavailability ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Plasma concentrations and bioavailability of clofibrinic acid have been estimated under conditions approaching the steady-state during a ten-day period of administration as clofibrate or as a calcium clofibrinate-carbonate combination (1:1 w/w) at a dosage interval of 12 h. Formulation — related differences in bioavailability were not significant, and the 95% confidence limits of these differences were within −2% to +8% of the mean for the reference formulation of clofibrate. The mean steadystate plasma concentrations of clofibrinic acid measured on the tenth day of dosing were 116 µg/ml±22 S.D. and 119 µg/ml±23 S.D. after administration of 885 mg as clofibrate and the calcium clofibrinate-carbonate combination respectively. The peaks of mean plasma concentrations were 70 µg/ml±15 S.D., 119 µg/ml±32 S.D. and 131 µg/ml±26 S.D. on the first, fifth and tenth day of dosing with clofibrate, and 62 µg/ml±13 S.D., 127 µg/ml±S.D. and 143 µg/ml±25 S.D. on the corresponding days of dosing with the calcium clofibrinate-carbonate combination. After the last dose on the tenth day of dosing, the mean apparent half-lives of elimination of clofibrinic acid from plasma were 24.2 h±4.4 S.D. and 25.5 h±3.2 S.D. after administration of clofibrate and the calcium clofibrinate-carbonate combination respectively.
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  • 36
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    European journal of clinical pharmacology 13 (1978), S. 69-72 
    ISSN: 1432-1041
    Keywords: Phenazone ; pharmacokinetics ; hydrocortisone ; elimination rate ; distribution volume
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The influence of a high plasma concentration of hydrocortisone on the metabolism of phenazone in humans has been studied. Two series of experiments were carried out, Group A to demonstrate any enzyme-inducing effect of hydrocortisone, and Group B to study the immediate effect of hydrocortisone on the metabolism of phenazone. 9 subjects (Group A) received a total 250–400 mg hydrocortisone i.m. twice daily for three days and the 24-hour elimination of phenazone was studied before and afterwards. In a further 5 subjects (Group B) the elimination of phenazone was examined during administration of hydrocortisone or placebo. The elimination rate and the apparent volume of distribution of phenazone remained unchanged under both experimental conditions.
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  • 37
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    European journal of clinical pharmacology 13 (1978), S. 97-101 
    ISSN: 1432-1041
    Keywords: Clonidine ; plasma level ; pharmacokinetics ; steady state ; urinary excretion ; side-effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary A single oral dose of clonidine 300 µg was administered to 8 healthy, normotensive subjects and the time course of its plasma concentrations was followed for 24 h. The plasma concentration of clonidine rose to a peak of 1.17±0.12 ng/ml at about 2 h: the absorption half-life was 0.6±0.2 h. Elimination followed first order kinetics with a half-life of 7.7±2.0 h. The correlation between the two most common side-effects of clonidine, sedation and dryness of the mouth, with the time course of its plasma concentrations was highly significant, p〈0.01. All the subjects complained of severe sedation. During continuous administration of clonidine (75 µg t.i.d.) for one week a steady state serum level of 0.30–0.35 ng/ml was achieved. One 75 µg tablet of clonidine raised the serum level to about 0.69±0.13 ng/ml in two hours. After cessation of dosing, the serum level declined with a half-life of 7.5±1.5 h. The urinary excretion of unchanged clonidine was found to be about onethird of the administered dose in 24 h during continuous administration and in the first 24 h after the single oral dose.
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  • 38
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    European journal of clinical pharmacology 14 (1978), S. 203-212 
    ISSN: 1432-1041
    Keywords: Mepivacaine ; pharmacokinetics ; neonates ; healthy adults ; metabolism ; renal excretion ; lignocaine
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics and metabolism of mepivacaine has been studied in premature neonates dosed subcutaneously and in healthy adults dosed intravenously. The pharmacokinetics of mepivacaine in four neonates (N) was compared with that in six adults (A). Newborns had a significantly longer terminal phase half-life than adults (N mean 8.69 h; A mean 3.17 h). Total plasma clearance normalized on body weight was significantly smaller in neonates (mean 2.34 ml/min/kg) than in adults (mean 5.47 ml/min/kg), as was the hepatic blood clearance (N mean 1.37 ml/min/kg; A mean 5.10 ml/min/kg). The renal plasma clearance, however, was significantly greater in neonates (mean 0.76 ml/min/kg) than adults (mean 0.20 ml/min/kg). There was an average six-fold increase in the fraction of the dose excreted unchanged in newborns (mean 43.3%) compared to adults (mean 7.1%) with acidified urine (pH 5.5–6.0). There was significantly more of the mono-N-demethylated metabolite of mepivacaine excreted by newborns (mean 11.4%) than by adults (mean 2.2%), but their capacity to carry out aromatic hydroxylation of mepivacaine was negligible. These results for mepivacaine were compared with those previously reported for lignocaine in premature infants. The immaturity of hepatic function appears to have diminished more profoundly the ability of premature infants to metabolize mepivacaine than lignocaine. These findings are discussed in terms of perfusion theory of hepatic drug elimination.
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  • 39
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    European journal of clinical pharmacology 14 (1978), S. 143-147 
    ISSN: 1432-1041
    Keywords: Children ; leukemia ; high-dose methotrexate ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of intravenous high-dose methotrexate were studied in two groups of children being treated for malignant diseases, mostly acute lymphatic leukemia. The peak serum level of methotrexate of 2.32·10−5 mol/l was found in children given 500 mg methotrexate/m2 by a 24 h infusion, and another group given 2790 mg/m2 during a 6 h infusion had serum levels as high as 2.16·10−4 mol/l. The decay of serum concentration of methotrexate after completion of the infusion followed a diphasic curve, with an initial serum half-life of 4.8 h, followed by a second half-life of 34.4 h at distribution equilibrium. The apparent volume of distribution was 56.8 litres/m2. Significant levels of methotrexate were found in cerebrospinal fluid, but penetration into cerebrospinal fluid was slow. Urinary excretion of methotrexate was considerable. Four to five days after commencement of the infusion, urinary concentrations of methotrexate still exceeded the serum levels.
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  • 40
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    European journal of clinical pharmacology 14 (1978), S. 335-340 
    ISSN: 1432-1041
    Keywords: Drug binding to muscle ; interindividual differences ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Binding of 22 drugs to human muscle tissue has been determined by ultrafiltration. All drugs tested were bound, the bound fraction ranging from 13% (aminophenazone) to 〉98% (desipramine). Both linear and nonlinear binding was observed. For chemically related substances, binding to muscle tissue correlated with plasma binding and lipid solubility. There were significant differences in binding to muscle from different individuals. With respect to pharmacokinetics of drugs, it is suggested that binding to muscle tissue may be at least as important as plasma binding.
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  • 41
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    European journal of clinical pharmacology 13 (1978), S. 41-48 
    ISSN: 1432-1041
    Keywords: Furosemide ; pharmacokinetics ; anephric patients ; metabolism ; protein binding
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of furosemide 40 mg i.v. were compared in 7 anephric patients and in 7 normal subjects. The average serum clearance was 66 ml/min in the patients and 219 ml/min in the normal subjects, and the corresponding weight corrected clearances were 1.33 ml/min · kg and 2.96 ml/min · kg. Binding to serum proteins was significantly decreased in the anephric subjects, in whom a significant negative correlation was found between the percentage binding and the volume of distribution VDss. In the patients, but not in the normal subjects, there was a significant positive correlation between $$V_{D_{ss} } $$ and serum clearance. Both in normal and anephric individuals 4-chlor-5-sulphamoylanthranilic-acid (CSA) was found, but there was no evidence of special accumulation either of CSA or anthranilic acid in the anephric patients. In the patients the initial increase in serum concentration of sodium and protein followed by a more conspicuous decrease were more pronounced, but none of the changes were statistically significant.
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  • 42
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    European journal of clinical pharmacology 13 (1978), S. 29-33 
    ISSN: 1432-1041
    Keywords: Microcrystalline theophylline ; chronic obstructive airways disease ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Plasma theophylline concentrations have been measured in 9 patients with chronic obstructive airways disease following the oral administration of a microcrystalline theophylline preparation. Some measurements of FEV1 were also made. Four patients were given 375 mg as a single dose and then subsequently 375 mg stat and 125 mg 4 times daily for 3 days, (Group I). A further 5 patients took 250 mg as a single dose and then 250 mg 4 times daily for 3 days, (Group II). In both groups, following the single dose and again after the last dose of chronic administration, blood samples were obtained at frequent intervals up to 24 h for plasma drug estimation. During the 3-day course, blood samples were drawn before and 2 h after each morning dose. In Group I patients, substantial plasma theophylline concentrations were seen only after the loading dose. Thereafter, the mean concentrations before or 2 h after the morning doese were always less than 4.0 µg/ml. Trough concentrations were usually below 2.0 µg/ml. In contrast patients in Group II achieved substantially higher plasma theophylline concentrations, with mean peak concentrations always 10 µg/ml or greater, and trough concentrations greater than 5 µg/ml on at least one occasion in every subject. The elimination half-lives after chronic administration in both groups were not significantly different from those obtained after single doses. Mean drug accumulation, measured as AUCss/AUC1, was 0.87±0.07 in Group I and 0.72±0.14 in Group II, indicating that accumulation had not occurred with either regimen. The mean increase in FEV1 2 h after the administration of a single dose was 19.2% after 375 mg and 16.7% after 250 mg. These results indicate that the recommended dosage regimen for microcrystalline theophylline preparation (375 mg stat and 125 mg 4 times daily) produces inadequate plasma theophylline concentrations: 250 mg 4 times daily would appear to be likely to result in satisfactory theophylline levels in more patients.
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  • 43
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    European journal of clinical pharmacology 13 (1978), S. 365-371 
    ISSN: 1432-1041
    Keywords: Etidocaine ; pharmacokinetics ; metabolism ; neonate
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The urinary elimination of etidocaine and several of its metabolites was investigated in neonates whose mothers had received one or more doses of etidocaine during labour. The urine collection period ranged among the neonates from 21.4 to 47.0 h post-partum. The total amounts of etidocaine and its metabolites recovered in neonatal urine represented a mean of 0.12 per cent of the maternal dose. Some differences in the pattern of urinary metabolites were observed between neonates and adults. Mean half-life of elimination of etidocaine calculated from sigma-minus plots of the neonatal urinary data was 6.42 h. This is greater than that previously reported following intravenous administration of etidocaine to adults (2.6 h). The slower rate of elimination in neonates is probably due to an increased neonatal volume of distribution since there is evidence to show that etidocaine is extensively metabolised by the neonate.
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  • 44
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    European journal of clinical pharmacology 13 (1978), S. 379-383 
    ISSN: 1432-1041
    Keywords: Antipyrine ; pharmacokinetics ; phenzone ; posture ; immobilization
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of a single dose of phenazone was studied in six subjects while ambulant and during bed rest for 3 days. Elimination of the drug was followed for 12 h after oral and intravenous administration. The elimination rate constant and total body clearance were significantly increased during bed rest as compared to the ambulant period, but the differences were small. The apparent volume of distribution decreased significantly. No consistent change due to bed rest was found in the rate of absorption or bioavailability of the oral dose.
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  • 45
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    European journal of clinical pharmacology 13 (1978), S. 209-212 
    ISSN: 1432-1041
    Keywords: Paracetamol ; acetaminophen ; Gilbert's syndrome ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of paracetamol after intravenous and oral administration has been studied in 6 patients with Gilbert's syndrome, and 6 healthy controls. Paracetamol clearance was significantly less in the patients (255 ml/min SE±23 ml/min) than in the normal subjects (352 ml/min SE±40 ml/min). Moreover, whilst paracetamol concentrations declined monoexponentially in the patients, the decline was biexponential in the controls. No difference in the bioavailability of 500 mg paracetamol given orally was observed between the two groups. The results suggest that not only is paracetamol elimination impaired in Gilbert's syndrome, but that its distribution kinetics are also abnormal. Both these findings could be attributed to a decrease in hepatic glucuronyl transferase activity.
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  • 46
    ISSN: 1432-1041
    Keywords: Aminopyrine ; pharmacokinetics ; 14CO2 breath test ; hepatic disease
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The time-course of aminopyrine in plasma and of14CO2 in breath was determined for 6 hours after oral administration of (14C-methyl) aminopyrine to healthy controls and to patients with hepatitis and hepatic fibrosis, cirrhosis and hepatic bilharziasis.14CO2 in breath declined about 1.8 times more slowly than aminopyrine plasma levels, which suggests the occurrence of metabolite demethylation. This was confirmed by the slow elimination of14C from plasma, the formation of14CO2 after aminopyrine had disappeared and the presence of a considerable amount of monomethyl-aminopyrine in plasma. The mean14CO2 concentration in breath was correlated with but was not proportional to aminopyrine clearance, which was attributed to individual differences in aminopyrine half-life. Both a correlation and proportionality were found when14CO2 extrapolated to zero time was used as a parameter of14CO2 production. Hepatic disease affected aminopyrine clearance to a variable extent. In the hepatitis and fibrosis group, aminopyrine clearance was affected in 2 out of five subjects. In all except one cirrhotic subject aminopyrine clearance was markedly decreased. Moreover, in three out of seven cases aminopyrine absorption was impaired, presumably due to decreased gastrointestinal blood-flow. This may produce an erroneously low14CO2 concentration in breath during the first two hours after aminopyrine administration. Hepatic bilharziasis was accompanied by very low aminopyrine clearance in all four cases. In two patients high apparent Vd values were observed, probably due to “first-pass” metabolism. Patients with ascites had Vd values within normal limits.
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  • 47
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    European journal of clinical pharmacology 14 (1978), S. 57-67 
    ISSN: 1432-1041
    Keywords: Chemotherapy ; sulfadiazine ; trimethoprim ; pharmacokinetics ; acetylation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Sulfadiazine (SDZ) 800 mg and trimethoprim (TMP) 160 mg were given orally to 10 normal subjects and the concentration of SDZ and TMP in serum and urine was followed for 24 h. Both drugs showed a significant negative correlation between individual “peak” concentrations in serum and the body weight of the subject. Twelve hours after dosing the serum concentration was 12 to 25 µg/ml for SDZ and 0.3 to 1.1 µg/ml for TMP. Individual concentration ratios between SDZ and TMP in serum were 4.8 (1 h) – 145 (24 h), and in the urine the ratio was close to 6 throughout the 24 h collection period. The range of urinary concentrations was from 65 to 400 µg/ml for SDZ and from 13.8 to 93.4 µg/ml for TMP. The fraction acetylated SDZ/acetylated SDZ + SDZ was 21% during the 0–8 h period, 33% during the 8–15 h period and 41% during the 15–24 period. The average values for the notional volume of distribution, Vd, were 0.36±0.13 1/kg for SDZ and 1.39±0.25 1/kg for TMP. The average “t1/2” was 15.2±7.4 h for SDZ and 7.4±1.9 h for TMP. Individual subjects showed a significant correlation between the serum clearance of TMP and SDZ (p〈0.01) and also between the renal clearance of the two drugs (p〈0.05). The serum clearance was significantly correlated with the renal clearance for TMP but not for SDZ. For SDZ Vd was significantly negatively correlated with the elimination constant; for TMP no such correlation was found. The serum clearance of SDZ was significantly correlated with the percentage of SDZ which was excreted as the (presumably) acetylated compound. The renal clearance of SDZ was independent of the serum concentration of SDZ. There was a highly significant negative correlation between the renal clearance and serum concentration of TMP, as well as for “acetylated SDZ”. The renal clearance of “acetylated SDZ” averaged more than six times that of unconjugated SDZ. With increased urine flow the renal clearances of TMP and SDZ were significantly increased.
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  • 48
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    European journal of clinical pharmacology 14 (1978), S. 237-244 
    ISSN: 1432-1041
    Keywords: Furosemide ; arterial hypertension ; protein binding ; sodium excretion ; renal function ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Furosemide 40 mg was injected intravenously in 7 patients with severe hypertension and vascular complications. A two compartment, open model was used to describe the disappearance of the drug from serum. The mean serum clearance (Cls=1.83 ml/min · kg) was significantly reduced compared to the mean Cls-value of a group of normals (2.96 ml/min · kg). A significant correlation was found between Cls and mean blood pressure, as well as between Cls and renal clearance (mean Clr=0.83 ml/min · kg); extrapolation of the regression line yielded a Cls-value of 50 ml/min for Clr=0. The Clr was also significantly negatively correlated with mean blood pressure. Protein binding of furosemide was normal, except in one patient, who had considerable impairment of renal function. Apparently more than 90% of unchanged furosemide passed in urine was excreted by tubular transport. A highly significant negative correlation was found between Cls and the fraction of furosemide excreted as a glucuronide. During the first two hours, significantly less sodium was excreted by the patients than by a comparable group of normal subjects. The correlation between serum concentration of furosemide and the amount excreted of sodium was not significant, but highly significant correlations were found between the amounts of furosemide and sodium excreted by the kidney in 0–30 and 0–60 min. In all the individual patients an approximately linear relationship with wide variation in the slope was found between the cumulative excretion of furosemide and sodium from 0–30 min to 0–60 and to 0–120 min. After 120 min deviations were observed in the curves from 4 of the patients, which indicated that smaller and smaller additional amounts of sodium were excreted with constant additional amounts of furosemide.
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  • 49
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    European journal of clinical pharmacology 14 (1978), S. 267-271 
    ISSN: 1432-1041
    Keywords: Lithium ; sustained-release ; pharmacokinetics ; manic patients
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary An ordinary and a sustained-release lithium carbonate preparation were administered acutely at equivalent dosage (1.80 g=24.3 mmol) in a crossover fashion to manic patients. Serum lithium levels were determined by atomic absorption spectroscopy and pharmacokinetic parameters were calculated. Maximum mean serum levels of 1.13 mmol/l and 0.78 mmol/l were achieved at 6 h and 12 h respectively with the ordinary and sustained-release forms. The mean half-lives of absorption, redistribution and elimination were 0.78 h±0.05 (SE), 5.06 h±0.23, 26.8 h±4.5 and 3.73 h±0.37 (SE), 4.42 h±0.28 and 25.6 h±5.5 for the ordinary and sustained-release forms respectively. In healthy volunteers the ordinary preparation was completely absorbed but only 85% of the sustained-release form was absorbed in the manic subjects. Lithium ion distributed into two kinetic compartments and the final compartment appeared to correspond to total body water.
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  • 50
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    European journal of clinical pharmacology 14 (1978), S. 277-280 
    ISSN: 1432-1041
    Keywords: Doxycycline ; iron ; charcoal ; enteral cycling ; man ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In order to study the intestinal interactions of doxycycline (DC) with Fe++ and charcoal, two groups of healthy volunteers were given either 200 mg or 100 mg DC in capsules at 2 p. m. and 9 p. m., and blood samples for fluorimetric assay of DC were collected for 24 h starting at 8.30 a. m. on the following morning. A 24-h-urine was also collected. The test was subsequently repeated at one-week intervals, when the volunteers also ingested either ferrous sulphate (80 mg Fe++) or charcoal (4.0 g) immediately after the zero-time sample of DC and at 3, 8 and 12 h. Charcoal completely adsorbed DC in vitro in an artificial small intestinal fluid. Ferrous sulphate or charcoal did not modify the serum level or urinary excretion of DC after the 200 mg+200 mg dose, but ferrous sulphate did reduce the 24-h urinary excretion of DC after the 100 mg+100 mg dose. The serum half-life and AUC of DC were reduced by ferrous sulphate given after the 100 mg+100 mg dose of DC. Charcoal did not modify any parameter, even after the 100 mg+100 mg dose of DC. The results do not support existence of important enteral cycling of DC. Although oral ferrous sulphate can lower the serum level and shorten the serum half-life of DC, the acute experiment suggested that a therapeutic serum level of DC can be maintained despite treatment with iron in the doses used in iron-deficiency, and charcoal in the doses used in diarrhoeic states, if the drugs are administered several hours apart.
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  • 51
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    European journal of clinical pharmacology 14 (1978), S. 69-73 
    ISSN: 1432-1041
    Keywords: Citalopram ; pharmacokinetics ; man ; steady state levels ; metabolism
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The plasma concentrations of citalopram, a potent serotonin reuptake inhibitor, and its demethylated metabolite have been determined by a specific fluorescence coupling technique during single dose experiments in volunteers and in clinical tests. Citalopram was found to have linear kinetics within the dose range investigated, which were characterized by fairly rapid absorption and slow elimination (biological half-life 1–21/2 days). Steady state levels in the range 120–340 nM (i.e. slightly above those associated with pharmacodynamic activity in animals) were attained within a week. A drug/metabolite ratio of 2–3 was recorded.
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  • 52
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    European journal of clinical pharmacology 14 (1978), S. 431-434 
    ISSN: 1432-1041
    Keywords: Timolol ; pharmacokinetics ; oral and intravenous dosing
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The plasma kinetics of timolol administered orally and intravenously to 5 male subjects were examined. Bioavailability was reduced by 25% when the drug was taken orally. Mean plasma half-life after oral dosing was 4.86 h, and after intravenous administration it was 4.56 h; the difference was not significant. The volume of distribution was 3.5 l/k. It is suggested that timolol is little affected by the ‘first pass effect’, even though there is marked interindividual variation in availability and peak plasma level.
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  • 53
    ISSN: 1432-0738
    Keywords: Cadmium ; Drug Metabolism ; Metallothionein ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The effect of acute and chronic cadmium administration on hepatic drug metabolism was investigated in the male rat. 3 days after the acute administration of cadmium by either the intraperitoneal (0.84 mg Cd/kg) or the oral (〉 80 mg Cd/kg) route, there was a significant potentiation in duration of hexobarbital hypnosis and inhibition of hepatic microsomal metabolism of hexobarbital and aniline. Administration of cadmium in the drinking water at levels of 100 or 200 ppm Cd for periods of 2–12 weeks or at levels of 5 or 20 ppm Cd for 50 weeks did not produce alterations in either drug response or hepatic drug metabolism. Significant levels of metallothionein, a cadmium binding protein, found in the liver of the rats receiving cadmium chronically may offer an explanation for the observed differences in drug metabolism between the acute and chronic administration of cadmium. In additional studies, pretreatment of the rats with subthreshold doses of cadmium (0.21 or 0.42 mg Cd/kg) intraperitoneally produced a tolerance to the alterations in drug metabolism induced by the previous cadmium dose (0.84 mg Cd/kg, i.p.). However, chronic cadmium treatment (5 or 20 ppm Cd for 50 weeks) did not impart any such tolerance to subsequently administered Cd (0.84 mg/kg) by the intraperitoneal route. The hepatic levels of metallothionein induced by the chronic cadmium treatment were only 30–60% of those induced by the subthreshold cadmium and thus may not have bound enough of the large challenge cadmium dose to produce the tolerance phenomenon.
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  • 54
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    Archives of toxicology 39 (1978), S. 267-287 
    ISSN: 1432-0738
    Keywords: Rat ; Plasma ; Alkaline phosphatase
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract This report describes the application of a test system which applies different substrates, inhibitors and acrylamide electrophoresis to the study of the alkaline phosphatase activity of rats. The system, which was specifically devised to characterise the alkaline phosphatase activity of small quantities of plasma from rats in toxicological studies, was also used to examine the plasma from rats under several physiological conditions, e.g. time of day, age, diet, etc. These physiological factors can influence the measurement of plasma alkaline phosphatase activity and should be taken into account when designing toxicological studies. Different experimental regimes were used to produce increases in liver, bone and intestinal alkaline phosphatase isoenzymes in the plasma of rats and these were reflected in the characterisations by the system. Although much remains unknown, a few concepts of rat plasma alkaline phosphatase activity emerged under our conditions. There is a ‘tidal’ intestinal component which arises from feeding and is approximately 60% of the total activity of the fed rat. In the fasted rat this ‘tidal’ component has largely disappeared and the ‘core’ activity which remains is composed of approximately equal proportions of bone isoenzyme and another as yet ill-defined component. The liver isoenzyme which appears in the plasma of the cholestatic rat appears to be either a very minor component or absent from the plasma of our normal CFE derived rat.
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  • 55
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    Archives of toxicology 40 (1978), S. 7-16 
    ISSN: 1432-0738
    Keywords: Thallium ; Furosemide ; Acetazolamide ; Renal elimination ; Oral absorption ; 204Tl ; Kidney ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Zusammenfassung Im Rahmen einer Untersuchung über das Schicksal von Thallium im Organismus und über den Einfluß von Diuretika auf die Eliminationsgeschwindigkeit dieses Giftes wurde Tl2SO4 (48.9 μmol = 10 mg/kg) an wachen Ratten oral verabreicht. Die Blutspiegel von Tl+ wurden anschließend als Funktion der Zeit ermittelt, sie konnten mit einer klassischen Bateman-Funktion nicht richtig beschrieben werden. Etwa l Std nach oraler Verabreichung war die Blutkonzentration maximal. Die Behandlung mit Furosemid (30 mg/kg) beschleunigte die Entfernung von Thallium aus dem Organismus auf signifikante Weise. Etwa 35% der zugeführten Menge Thallium wurde während einer Woche nach der Injektion dieses Diuretikums mit dem Urin ausgeschieden. Auch die Ausscheidung von Natriumionen und Wasser war signifikant erhöht, die von Kaliumionen blieb jedoch fast unverändert. Thallium selbst verursachte eine schwache diuretische Wirkung. Nach fortgesetzter Behandlung mit Furosemid (bis 2 Wochen) blieb die Eliminationsgeschwindigkeit von Thallium, Wasser und Natrium beschleunigt, während die Ausscheidung von Kaliumionen im Vergleich zu Kontrolltieren etwas herabgesetzt war. Ethacrynsäure verursachte nach wiederholter Gabe in diuretisch wirksamen Dosen eine retroperitoneale Fibrose. Dieses wirksame Diuretikum konnte daher nicht in die Untersuchung einbezogen werden. Acetazolamid (30 mg/kg) erhöhte ebenfalls die Ausscheidung von Thallium, vor allem innerhalb der anfänglichen 24 Std. Die Wirkung war weniger intensiv als die von Furosemid, sie war außerdem bald erschöpft. Die Ergebnisse legen den Schluß nahe, Furosemid in hohen Dosen sei eine wirksame Maßnahme zur Beschleunigung der Thalliumentfernung aus dem Organismus, zumindest im vorliegenden Tiermodell. Acetazolamid ist zu diesem Zwecke wahrscheinlich nicht geeignet.
    Notes: Abstract In connection with a programme of investigations concerning the disposition of thallium in the rat and the influence of diuretic agents on the rate of elimination of thallium from the body, Tl2SO4 (48.9 μmol = 10 mg/kg) was given by mouth to conscious rats. Blood levels were studied as a function of time. They could not be described adequately by means of a classical Bateman function. The maximum blood level was achieved approximately 1 h following oral ingestion. Treatment with furosemide for 11 days (30 mg/kg twice daily) significantly accelerated the removal of thallium from the body with the urine. Approximately 35% of the administered thallium was excreted within one week following the injection of this diuretic agent. The excretion of sodium and water was also considerably enhanced, that of potassium hardly changed. Thallium itself displayed weak diuretic activity. Upon prolonged treatment (1–2 weeks) with furosemide the elimination of thallium, water and Na+ was still accelerated, although that of potassium proved diminished with respect to controls. Ethacrynic acid when administered repeatedly in appropriate doses caused retroperitoneal fibrosis. Therefore, this potent diuretic agent was not included in the investigations. Acetazolamide (30 mg/kg) also enhanced the excretion of thallium, especially within the initial 24 h of treatment. The effect was less pronounced than that of furosemide and rapidly exhausted. The results suggest that furosemide in a high dose is effective in accelerating thallium elimination from the body in the present animal model. Acetazolamide is probably not suitable for this purpose.
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  • 56
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    Archives of toxicology 41 (1978), S. 99-105 
    ISSN: 1432-0738
    Keywords: Rat ; Method ; Gastric ulceration ; Distention of stomach ; Stress ; Anti-inflammatory drugs ; Ulcerogenic side effect
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Zusammenfassung Das sog. „distention“-Ulkus wurde an Albinoratten untersucht und als neue Möglichkeit für die Feststellung ulzerogener Nebenwirkungen von Substanzen beschrieben. Die Dehnung des Magens in sich war nicht ausreichend um ulzerogene Läsionen auszulösen, denn die Dehnung des Magens mit physiologischer Kochsalzlösung führte nicht zur Ulzeration. Die Säure ist ein entscheidender Faktor in der Bildung des „distention“-Ulkus. Große Volumina von 0,1 N Salzsäure riefen innerhalb von 1 Std massive Ulzeration hervor. Kleine Mengen von dieser Säurelösung verursachten keine Ulzeration im Magen. Entzündungshemmer, die in noch von ulzerogenen Nebenwirkungen freien therapeutischen Dosen verabreicht wurden, erhöhten die Empfindlichkeit der gastralen Mukosa dem aggressiven Faktor, der Säure, gegenüber. Bei den mit bekanntlich ulzerogen wirkenden Dosen von Entzündungshemmern vorbehandelten Ratten wurde eine schnellere Bildung von Ulzera durch die Dehnung des Magens mit Säure beobachtet. Auch die Stressvorbehandlung beschleunigte und verstärkte die Bildung der durch Dehnung hervorgerufenen ulzerogenen Veränderungen im Magen.
    Notes: Abstract A modification of the distention ulcer was studied in albino rats and a new possibility of testing ulcerogenic side effects of drugs was described. The distention alone was not sufficient to produce lesions. The severity of ulcer lesions was highly dependent on the volume of the acid solution. Large volumes of 0.1 N HCl evoked severe ulcers within 1 h. Small amounts of weak acid solution did not cause any ulceration. Anti-inflammatory drugs administered in therapeutic doses, which did not yet produce any ulcers in animals, increased the sensitivity of the gastric mucosa against the aggresive factor, the acid. In animals pretreated by anti-inflammatory drugs in toxic doses an earlier development of ulceration was observed by distention with acid. Stress also accelerated and aggravated the formation of distention ulcers.
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  • 57
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    Archives of toxicology 39 (1978), S. 249-266 
    ISSN: 1432-0738
    Keywords: Rat ; Alkaline phosphatase ; Plasma ; Organs ; Toxicity testing
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract A manual system of various estimations of rat plasma alkaline phosphatase activity has been devised for small volumes of plasma which uses different inhibitors, compares the utilisation of two substrates and includes acrylamide gel electrophoresis. The different inhibitors etc. allow a degree of discrimination between alkaline phosphatase extracts of rat organs. The properties of isoenzymes, e.g. intestinal alkaline phosphatase, differ depending upon the environment in which they are studied. In conjunction, if necessary, with the methods described for the estimation of liver and intestinal alkaline phosphatase activity, it is hoped to use the system to discriminate between the isoenzymes present in the plasma alkaline phosphatase of rats in toxicological studies.
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  • 58
    ISSN: 1432-1041
    Keywords: Lignocaine ; pharmacokinetics ; neonates ; metabolism ; renal excretion ; plasma concentrations
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics and metabolism of lignocaine in premature neonates was studied after subcutaneous administration. The collection of serial urine together with a limited number of blood samples from neonates enabled simultaneous computer fitting of data to a pharmacokinetic model. The disposition kinetics of lignocaine in four neonates were compared with similar data reported for adults. Neonates had prolonged t1/2 (neonate mean: 3.16 h; adult mean: 1.80 h), and an increased total volume of distribution (neonate mean: 2.75 l/kg; adult mean: 1.11 l/kg) compared with adults. Total plasma clearance (Cltp) normalised on body weight showed no significant difference between neonates (mean: 0.610 l/h/kg) and adults (mean: 0.550 l/h/kg). The urinary excretion of lignocaine and several of its metabolites was studied in 8 neonates and 11 adults. Neonates were shown to excrete much more unchanged lignocaine (mean: 19.67%) compared with adults (mean: 4.27%) and the proportion of the dose excreted as 4-hydroxyxylidine is considerably reduced in neonates (neonate mean: 8.89%; adult mean: 63.78%). The use of the two pharmacokinetic parameters, t1/2 and Cltp, as indices of drug elimination ability are discussed.
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  • 59
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    European journal of clinical pharmacology 13 (1978), S. 219-222 
    ISSN: 1432-1041
    Keywords: Glaziovine ; pharmacokinetics ; plasma levels ; urinary excretion ; biliary excretion ; enteral absorption
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetic parameters of Glaziovine, a pro-aporphine alkaloid with neuropharmacological properties, were investigated in healthy human volunteers. Glaziovine-14C 20 mg was administered in capsules (oral route) and in vials (i.v. route). Total radioactivity was measured in plasma, urine and faeces. When administered orally, peak plasma levels were encountered at 2 h. The cumulative urinary excretion of total radioactivity over a 24 h period was 38% after oral and 50% after i.v. administration. Investigation of metabolites in urine revealed Glaziovine glucuronide as the sole metabolite of the drug. By comparing the percentage of urinary excretion or the area under the plasma level-time curve (AUC) obtained in the first 24 hours after i.v. and oral administration, enteral absorption was found to range from 78 to 84%. Thus, glaziovine appears to show very high enteral absorption.
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  • 60
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    European journal of clinical pharmacology 13 (1978), S. 55-60 
    ISSN: 1432-1041
    Keywords: Valproic acid ; pharmacokinetics ; liver disease
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The disposition of valproic acid (di-n-propylacetate; VA) has been studied after a single oral dose of a solution of 450 mg in 7 patients with alcoholic cirrhosis and in 4 patients recovering from acute hepatitis. The diagnosis was based on biochemical function tests and histological findings. The pharmacokinetic parameters were compared with those reported for healthy volunteers. VA in therapeutic concentration (80 µg/ml) in plasma was less bound to plasma proteins in patients with alcoholic cirrhosis (70.7±11.3%) and in patients recovering from acute hepatitis (78.1±14.1%) than in controls (88.7±5.2%). The reduced binding affected the blood/plasma concentration ratio and the apparent distribution volume Vd(β); the latter was increased from the normal value of 0.14±0.05 l/kg to 0.22±0.09 (p〈0.05) in alcoholic cirrhotics, and to 0.20±0.07 (p=0.056) in patients recovering from acute hepatitis. The half-life of elimination T1/2 (β) (controls=12.2±3.7 h) was significantly (p〈0.05) prolonged in cirrhotics (18.9±5.1 h) and in patients recovering from acute hepatitis (17.0±3.7 h). The plasma $$\overline {Cl} $$ of total drug was not impaired, which can best be explained by the lower plasma protein binding, which might have increased the $$\overline {Cl} $$ of this drug which shows restricted clearance. In addition, the plasma $$\overline {Cl} $$ of free drug was significantly (p〈0.02) reduced in alcoholic cirrhotics. During a two day urine collection no measurable amount of unchanged VA was recovered. There was considerable excretion of VA-conjugates, which could be hydrolyzed either by HCl or by β-glucuronidase/arylsulphatase (4–23% of the dose). These percentages were in the same range as in normals (26.7±16.1%). The study indicates that elimination of VA is slightly impaired in patients with dysfunction of the liver.
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  • 61
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    European journal of clinical pharmacology 13 (1978), S. 267-274 
    ISSN: 1432-1041
    Keywords: Chlordiazepoxide ; benzodiazepines ; pharmacokinetics ; bioavailability ; intramuscular injection ; alcohol withdrawal
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The absorption of oral and intramuscular (i. m.) chlordiazepoxide hydrochloride (CDX · HCl) was compared in two pharmacokinetic studies. In Study One, single 50-mg doses of CDX · HCl were administered orally and by i. m. injection to 14 healthy volunteers using a crossover design. Whole-blood concentrations of chlordiazepoxide (CDX) and its first active metabolite, desmethylchlordiazepoxide (DMCDX), were determined in multiple samples drawn after the dose. Mean pharmacokinetic variables for CDX following oral and i. m. administration, respectively, were: highest measured blood concentration, 1.65 vs 0.87 µg/ml (p〈0.001); time of highest concentration, 2.3 vs 7.6 h after dosing (p〈0.001); apparent absorption half-life, 0.71 vs 3.39 h (p〈0.001). Biphasic absorption after i. m. injection, consistent with precipitation at the injection site, was observed in 9 of 14 subjects. Based upon comparison with previous intravenous data, the completeness of absorption was 100% for oral vs 86% for i. m. CDX · HCl (p〈0.1). In Study Two, 28 male chronic alcoholics with clinical manifestations of the acute alcohol withdrawal syndrome were randomly assigned to one of four treatment conditions: 50 or 100 mg doses of CDX · HCl, by mouth or by i. m. injection. Concentrations of CDX and DMCDX, determined in plasma samples drawn every 20 min for 5 h following the dose, were significantly higher after oral administration of a given dose than at corresponding points in time after i.m. injection after the same dose. Thus absorption of oral CDX is reasonably rapid and complete, whereas the absorption rate of i. m. CDX is slow.
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  • 62
    ISSN: 1432-1041
    Keywords: Phenylbutazone ; pharmacokinetics ; model ; retrospective analysis ; digestive-tract hemorrhage
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Phenylbutazone treatment can cause digestive-tract hemorrhages, but its concentration in the blood at the time of hemorrhage is generally not known. In two patients who had had digestive tract hemorrhages, the variation in the serum phenylbutazone concentration throughout treatment and just before hemorrhage was simulated by a two-compartment model based on assays (gas-liquid chromatography) made after the hemorrhage. Identification of the parameters of the model and simulation of changes in concentration during therapy suggested that the phenylbutazone level in serum at the time of hemorrhage was 101 and 125 µg/ml respectively.
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  • 63
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    European journal of clinical pharmacology 14 (1978), S. 29-37 
    ISSN: 1432-1041
    Keywords: Hydroflumethiazide ; pharmacokinetics ; cardiac failure ; renal drug excretion ; metabolism ; 2,4-disulfamyl-5-trifluoro-methylaniline
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of hydroflumethiazide (HFT) were investigated after single oral doses of 6 µmoles/ per kg body weight in five healthy subjects and in nine patients with moderate cardiac failure. HFT was excreted in urine together with 2,4-disulfamyl-5-trifluoromethylaniline (DTA), which was also present in the blood after administration of HFT. HFT and DTA were determined by TLC and spectrofluorodensitometry. Mean cumulative urinary excretion of HFT was 46.5 and 47.5 per cent of the dose both in healthy subjects and in patients. Distribution half-life (t1/2α) was about 2 h in both groups of subjects, while biological half-life (t1/2β) ranged from 12.4 to 26.9 h (mean 16.6) in healthy subjects, and from 6.3 to 13.7 h (mean 9.6) in patients. Mean renal clearance was 0.33 and 0.211 · h−1 · kg−1 in normal subjects and patients, respectively, and was almost equal to the total body clearance. HFT had a large apparent volume of distribution (Vβ), with mean values of 6.4 and 3.11 · kg−1 in normal subjects and patients. Mean cumulative urinary excretion of DTA was 1.8 and 1.9 per cent in healthy subjects and patients with cardiac failure. The apparent half-life of DTA, determined from urinary excretion rate in eleven subjects, ranged from 16 to 56 h but half-lives in three others were more than 100 h. The results indicate that HFT is partly metabolized in the body to DTA, and DTA and HFT are excreted in urine. The half-life of DTA was longer than that of the parent drug. The apparent volume of distribution, clearance and biological half-life of HFT were lower in patients with cardiac failure than in healthy subjects.
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  • 64
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    European journal of clinical pharmacology 14 (1978), S. 361-366 
    ISSN: 1432-1041
    Keywords: Furosemide ; gestosis of pregnancy ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Furosemide 50 mg was administered orally and intravenously to twelve gestotic women for brief periods as a part of a randomized, multicentre clinical trial comparing the efficacy of bed rest and pharmacological treatment. The pharmacokinetic profile was investigated using a gas-liquid chromatographic technique. The plasma half-life after oral and intravenous administration was 115±37.1 and 71.8±26.3 min and plasma clearance was 153±48 and 152±23 ml/min, respectively (mean±SD). Comparative data from healthy pregnant women cannot be obtained for ethical reasons. The results show that gestosis has only a marginal if any effect on the kinetics of furosemide in comparison with published kinetic parameters in healthy volunteers and patients with renal failure. The new-born babies where checked for side effects according to a protocol in use in a larger regional surveillance programme. No clinical side-effects were attributable to furosemide, but the small size of the group does not permit any definitive conclusions about this aspect.
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  • 65
    ISSN: 1432-1041
    Keywords: Phase I clinical trial ; complex protocol ; tolerance ; pharmacokinetics ; praziquantel ; anthelmintic
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The tolerance of Praziquantel (2-cyclohexylcarbonyl-1, 3, 4, 6, 7, 11b-hexahydro-2H-pyrazino-[2, 1-a]isoquinoline-4-one) in oral doses of 1×20 mg/kg, 1×50 mg/kg, 3×10 mg/kg and 3×25 mg/kg body weight (τ=4 h) was tested in a complex study involving 36 healthy volunteers. In addition to the usual assessment of clinical chemistry, haematology, coagulation physiology, urinalysis, clinico-physiological examination including EEG, and medical examination, clinico-psychological parameters were also recorded and special neurological investigations were performed. No clinically relevant changes were found in any of the laboratory parameters, nor in the medical-neurological or clinico-physiological examinations. Based on a few clinicopsychological parameters and subjective comments, the largest daily dose tested (3×25 mg/kg=75 mg/kg) produced a slight, transient disturbance in general well-being, which was barely detectable on objective clinical examination. The pharmacokinetic behaviour was dominated by rapid metabolism and pronounced first-pass metabolism of praziquantel, which greatly limits the value of results obtained by GC analysis of unchanged drug in serum. The peak concentration in serum was reached after 1– h, and the elimination half-life for the period 2–8 h was 1–1.5 h.
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  • 66
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    European journal of clinical pharmacology 13 (1978), S. 35-39 
    ISSN: 1432-1041
    Keywords: Norethindrone ; bioavailability ; man ; competitive protein binding ; sex differences ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary A competitive protein binding assay for norethindrone was developed to measure plasma levels in human subjects. The plasma levels were considerably higher in women than in men, especially at low dose levels. The plasma levels were directly related to the dose in men; but greater variations in the plasma levels were observed in women. The plasma half-life was about 5 h in both sexes with single oral doses of 5 to 20 mg. A comparative bioavailability study with norethindrone from 2 different manufacturers, formulated in the same manner, showed no significant differences in absorption characteristics and provided sufficient data for pharmacokinetic analysis.
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  • 67
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    European journal of clinical pharmacology 13 (1978), S. 119-124 
    ISSN: 1432-1041
    Keywords: Bendroflumethiazide ; pharmacokinetics ; hypertension ; renal clearance
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary After four weeks on placebo treatment, 8 hypertensive patients (WHO stage I) were treated for 2 weeks with bendroflumethiazide (bft) 2.5 mg and KCl 1.5 g daily. Subsequently they received bft 5 mg and KCl 1.5 g daily for a further fortnight. At the end of each period of treatment blood pressure was recorded and blood samples and urine were collected for analysis of bft by GLC. Before taking the daily dose of bft, no trace of the drug was found in plasma. Peak levels of bft were seen after 2.3 h and averaged 23 and 50 ng · ml−1 after 2.5 and 5 mg, respectively. After bft 2.5 mg the plasma level was too low for kinetic analysis. The plasma half-life after 5 mg averaged 4.1 h. The mean apparent volume of distribution was 1.18 l · kg−1. Non-renal clearance averaged 200 ml · min−1. The renal clearance of bft was significantly lower (p〈0.05) after 5 mg (48 ml · min−1) than after 2.5 mg bft (93 ml · min−1), although the creatinine clearance remained unchanged. No correlation was found between the plasma level of bft and its effect on blood pressure.
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  • 68
    ISSN: 1432-1041
    Keywords: Cephacetrile ; pharmacokinetics ; renal Impairment
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of cephacetrile, administered as a single i. v. injection of 15 mg/kg, have been determined in 8 patients with normal renal function and in 12 patients with a varying degree of renal impairment. A two-compartment model was used to describe the biphasic decline in serum concentrations and to calculate the amount of antibiotic in the central and peripheral compartments. In patients with normal renal function the following values were obtained for various pharmacokinetic parameters: α=3.971 h−1; β=0.343 h−1; K12=1.745 h−1; K21=0.763 h−1; Kel=1.793 h−1; Vc=8.181; Vp=18.401 and Vdss=26.581. Cephacetrile had some of the highest apparent distribution volumes of all the cephalosporins. Impaired renal function significantly affected α, β, K12, and Kel. A linear relationship between Kel of cephacetrile and creatinine clearance was demonstrated. The elimination of cephacetrile in anuric patients was about ten times slower than in patients with normal renal function.
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  • 69
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    European journal of clinical pharmacology 14 (1978), S. 293-299 
    ISSN: 1432-1041
    Keywords: Breath analysis ; 14CO2 exhalation ; drug metabolism ; glycodiazine ; liquid chromatography ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Exhalation of14CO2 in breath has been used to assess the rate of hepatic demethylation of (14C-dimethyl)aminopyrine, but due to the complexity of aminopyrine metabolism the pharmacokinetics of the procedure are insufficiently understood. Therefore, studies were performed in five individuals after oral administration of (14C-methoxy)glycodiazine, a model substance with relatively simple kinetic properties. Plasma concentrations of the drug and urinary output of its metabolites measured by high pressure liquid chromatography were analysed by a two-compartment open model. The terminal disappearance of14CO2 from breath was practically identical with the terminal disappearance of glycodiazine from plasma, which could be correlated with the plasma clearance of free glycodiazine. The mean transit time of14C-atoms from plasma to breath was 3 h. These results contribute to the pharmacokinetic basis for use of14C-demethylation breath tests. In particular, they are consistent with the hypothesis that14CO2-breath analysis may be used to assess certain pharmacokinetic parameters of appropriately labelled test compounds. These parameters may not necessarily be a direct reflection of the rate of demethylation.
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  • 70
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    European journal of clinical pharmacology 14 (1978), S. 405-412 
    ISSN: 1432-1041
    Keywords: Colloidal plasma substitutes ; cross-linked polypeptides ; Haemaccel® ; pharmacokinetics ; renal failure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Infusions of 3.5% isocyanate cross-linked polypeptide solution 500 ml were given to 52 patients with normal or impaired renal function: glomerular filtration rate (GFR)=0–133 ml/min. The serum concentration and urinary excretion of hydroxyproline were measured and the equivalent polypeptide concentrations were calculated from the results. In patients with normal renal function (GFR〉90 ml/min) the proportion of polypeptide excreted in the urine up to 12 h was 45.4±2.6% ( $$\bar X$$ ±SEM), up to 24 h 47.7±2.9% and up to 48 h 49.3±3.4%. In patients with moderate renal insufficiency (GFR=30–90 ml/min) there was no decrease in polypeptide excretion and even in patients with more serious impairment of GFR (11–30 ml/min) 48-h urinary polypeptide excretion was still 40.6±5.9%. In patients with GFR of 2–10 ml/min polypeptide excretion fell to 10.7±3.2% during the first 12 h, although there was an increase in later collection periods as compared to patients with normal renal function −19.9±3.9% in 24 h and 27.0±3.5% in 48 h. The elimination half-life (t1/2) calculated from serum concentrations was 505±30 min ( $$\bar X$$ ±SEM) in patients with normal renal function (GFR〉90 ml/min). Only when the GFR fell below 30 ml/min did it slowly begin to increase. In patients with minimal residual renal function (GFR=0–0.5 ml/min), who were on haemodialysis, the elimination half-life was 985±49 min, i.e. approximately twice the normal. Twice weekly infusion of 3.5% polypeptide solution 500 ml over a period of 6 weeks did not produce any significant cumulation in haemodialysis patients (GFR=0–0.5 ml/min). A weekly dose of polypeptide 35 g appeared to be quite safe when given for several weeks, even to anuric patients. As no significant amount of polypeptide was lost during haemodialysis, the dose can be chosen without taking into account any effect of intermittent haemodialysis.
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  • 71
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    Journal of cancer research and clinical oncology 91 (1978), S. 157-164 
    ISSN: 1432-1335
    Keywords: MNU ; DNA Repair ; Rat ; Age
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary DNA repair time-course was studied after injury by N-methyl-N-nitrosourea (MNU) in rat liver cells of animals of different ages and in fetuses using hydroxyurea (HU) as inhibitor of scheduled DNA synthesis. DNA repair was a rapid phenomenon, more so in young adults than in newborns, and was not detectable in fetuses. A correlation seems to exist among organ sensitivity to carcinogen, age of animal and DNA repair.
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  • 72
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    Journal of molecular medicine 56 (1978), S. 309-310 
    ISSN: 1432-1440
    Keywords: Perhexilin-Maleat ; generalisierte Lipidose ; Ratte ; Perhexiline maleate ; Generalized lipidosis ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Summary Administration of perhexiline (Pexide®) to rats causes generalized occurrence of lamellated and crystalloid cytoplasmic inclusions which resemble those described in patients with perhexiline-induced polyneuropathy. It is concluded that perhexiline being an amphiphilic cationic compound is a potent inducer of generalized lipidosis.
    Notes: Zusammenfassung Perhexilin (Pexid®) verursacht bei der Ratte das generalisierte Auftreten von lamellären und kristalloiden zytoplasmatischen Einschlußkörpern, die denjenigen gleichen, die bei Patienten mit Perhexilin-induzierter Polyneuropathie beschrieben worden sind. Aus den vorgelegten Befunden wird geschlossen, daß Perhexilin, eine amphiphile kationische Verbindung, ein starker Induktor einer generalisierten Lipidose ist.
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  • 73
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    Naunyn-Schmiedeberg's archives of pharmacology 302 (1978), S. 239-254 
    ISSN: 1432-1912
    Keywords: Myocardial α-adrenoceptors ; Rat ; Guinea pig ; Cat ; Hypothyroidism ; Single adrenoceptor type
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The presence and distribution of myocardial α-adrenoceptors in different parts of the heart of various mammalian species was investigated. For this reason experiments were performed in isolated cardiac preparations of rats, guinea pigs and cats. In order to obtain more information about the nature of the cardiac α-adrenoceptors additional experiments were undertaken at different temperatures. These studies were aimed to show whether or not a conversion of β-to α-adrenoceptors or vice versa takes place. Moreover, we analyzed the influence of hypothyroidism on the sensitivity of α- and β-adrenoceptors of preparations from rats fed with propylthiouracil. Finally, we tried to find out whether stimulation of these α-adrenoceptors leads to the formation of the cyclic nucleotides cAMP and cGMP. The following results were obtained: 1. In right ventricular strips of rats, guinea pigs and cats phenylephrine stimulated α-adrenoceptors. After blockade of β-adrenoceptors the respective pD2-values of phenylephrine were 5.32, 5.99 and 5.33. The doseresponse curves obtained in the presence of α-adrenolytic drugs were shifted to the right without depression of the maximum. In the rat, in addition, the pA2-values for the α-adrenolytic drugs yohimbine (5.79) and phentolamine (7.85) were determined. They were at least 0.5 log units higher than those found in the rat for other α-adrenoceptors (Van Rossum, 1965) thus supporting the view that the population of cardiac α-adrenoceptors is different from that of other organs. In left ventricular strips of guinea pigs the pD2-value for the α-mimetic effect of phenylephrine was of the same order of magnitude as that obtained in the right ventricle. 2. In the papillary muscle of the right ventricle of guinea pigs and cats phenylephrine stimulated α-adrenoceptors. 3. In the left atrium of the rat, phenylephrine stimulated myocardial α-adrenoceptors (pD2: 5.58). Also in this preparation the pA2-values for yohimbine (6.36) and phentolamine (8.21) were different from those found for other α-adrenoceptors in the rat (Van Rossum, 1965). Likewise in strips from the left atrium of the cat myocardial α-adrenoceptors are present. 4. In spontaneously beating right atria of the rat a clear-cut positive chronotropic effect mediated by stimulation of α-adrenoceptors could not be demonstrated although in 6 out of 15 preparations a small positive chronotropic effect became evident. No positive chronotropic effect at all was obtained by stimulation of α-adrenoceptors in the cat right atrium. 5. In ventricular strips as well as in left atria from hypothyroid rats the pD2-value for the α-effect of phenylephrine was increased, in the atrium more than in the ventricle, while the pA2-values for yohimbine and phentolamine were not significantly different from the controls. Under these conditions a distinct positive chronotropic effect mediated by stimulation of α-receptors was found in the spontaneously beating rat atrium. 6. After stimulation of α-adrenoceptors in atria and ventricular strips of normal and propylthiouraciltreated rats, as well as in strips of guinea-pig ventricles or cat atria no elevation of cAMP and cGMP was observed. 7. The concept of a single adrenoceptor convertible from α- to β-type or vice versa was not supported by our experiments. These were carried out at different temperatures on left atria and on ventricular strips of rat hearts using the irreversible α-adrenoceptor blocking agent phenoxybenzamine. 8. The present experiments provide evidence for the existence of α-adrenoceptors in the myocardium of various mammalian species. Their stimulation produces positive inotropic effects without increases in heart rate.
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  • 74
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    Naunyn-Schmiedeberg's archives of pharmacology 303 (1978), S. 251-256 
    ISSN: 1432-1912
    Keywords: Diurnal rhythm ; Motor activity ; Rat ; H 44/68 ; FLA 63 ; Animex
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The effects of the inhibitor of the tyrosine-hydroxylase H 44/68 and the inhibitor of the dopamine-β-hydroxylase FLA 63 on the diurnal variations of the motor activity was studied in male Wistar rats, which were kept under standardized conditions of light and darkness (L:D=12:12h). The motor activity was continuously registered in groups of 5 rats using a two-channel Animex motimeter. During light FLA 63 (40 mg/kg, s.c.) greatly increased motor activity on acute application and during darkness the physiological elevation in motor activity was further but slightly increased. H 44/68 (200 mg/kg, i.p.) also increased motor activity during light, but in contrast to FLA 63 greatly reduced motor activity during darkness. The results indicate that though dopamine and noradrenaline are involved in the regulation of behavioural components, one or the other catecholamine may play a predominant role at different times of the day. Thus, it seems worthwhile to study the effects of drugs separately during light and during darkness.
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  • 75
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    Naunyn-Schmiedeberg's archives of pharmacology 303 (1978), S. 257-261 
    ISSN: 1432-1912
    Keywords: Diurnal rhythm ; Central noradrenaline and dopamine turnover ; H 44/68 ; FLA 63 ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Under controlled conditions of environmental light and darkness of 12:12 h the turnover of dopamine and noradrenaline in brain of male Wistar rats was studied at different times of the day. The turnover was calculated from the decline of the amine concentrations either after inhibition of the tyrosine-hydroxylase with H 44/68 (200 mg/kg, i.p.) or after inhibition of the dopamine-β-hydroxylase with FLA 63 (40 mg/kg s.c.). Whereas the noradrenaline turnover showed only slight but not significant variations within 24 h, the turnover of the central dopamine exhibited significant variations with increased turnover rates in the second half of the light and first half of the dark period. Thus, diurnal variations have to be taken into account when studying the effects of drugs on the turnover of biogenic amines in the central nervous system.
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  • 76
    ISSN: 1432-1912
    Keywords: Gastric secretion ; Cyclic AMP ; Phosphodiesterase inhibitor ; Rat ; Guinea pig
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The effect of the phosphodiesterase inhibitor 4-(3-cyclopentyloxy-4-methoxyphenyl)-2-pyrrolidone (ZK 62711) on gastric secretion and the cyclic AMP system of the gastric mucosa was studied in rats and guinea pigs. In rats, 0.03–0.3 μmoles/kg ZK 62711 i.v. stimulated acid and pepsin secretion in a dose-dependent manner and 0.03 μmoles/kg i.v. enhanced the effect of histamine. In guinea pigs no reproducible stimulation was found after intravenous injections of ZK 62711. The stimulation of gastric secretion in the rat by 0.3 μmoles/kg ZK 62711 i.v. was not affected by vagotomy but was totally inhibited by 10 μmoles/kg cimetidine i.v. The structurally related phosphodiesterase inhibitor, 4-(3-butoxy-4-methoxybenzyl)-2-imidazolidine (Ro 20-1724), at the dose of 3.3 μmoles/kg i.v. stimulated gastric secretion in anaesthetised rats to a similar extent as 0.3 μmoles/kg ZK 62711 i.v. The content of cyclic AMP in the rat gastric mucosa in vivo was slightly increased by 10 μmoles/kg ZK 62711 i.v, whereas lower doses did not change it. Accumulation of cyclic AMP in the rat gastric mucosa by 50 μmoles/kg histamine i.v. was enhanced by simultaneous injections of 3.3 μmoles/kg ZK 62711 i.v. In rat gastric tissue slices in vitro 1–50 μM ZK 62711 increased the level of cyclic AMP but 100 μM histamine had no effect in the absence or presence of ZK 62711. In gastric mucosal slices of the guinea pig 10 and 50 μM ZK 62711 increased the cyclic AMP content which effect was inhibited by 100 μM cimetidine and enhanced the stimulatory effect of 100 μM histamine on cyclic AMP. The activity of soluble cyclic AMP phosphodiesterase was inhibited by ZK 62711 in the rat (IC50=18 μM) and guinea pig gastric mucosa (IC50=1.5 μM). Adenylate cyclase was not affected in the homogenate of the guinea pig gastric mucosa. The results indicate that the phosphodiesterase inhibitor ZK 62711 which increases cyclic AMP levels in the gastric mucosa in vivo and in vitro, is a potent stimulator of gastric acid secretion.
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  • 77
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    Cell & tissue research 189 (1978), S. 155-166 
    ISSN: 1432-0878
    Keywords: Levator ani muscle ; Rat ; Neuromuscular junction ; Castration ; Testosterone effect
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Summary The ultrastructure of the neuromuscular junction (n.m.j.) of the androgen-sensitive levator ani muscle was studied in normal adult male rats, in 8-month-old rats castrated at the age of one month and in castrated rats treated with testosterone propionate (TP). Castration does not result in significant changes of the n.m.j. The density of synaptic vesicles and the postsynaptic junctional folds remain practically normal in spite of marked atrophy of the muscle. TP administration for 7 days results in marked changes in preand postsynaptic structures. There is slow progressive depletion of synaptic vesicles, appearance of cisternae and coated vesicles in axon terminals, and coalescence of coated vesicles with the plasma membrane. Coated vesicles are also found inside Schwann cells and among junctional folds. Dense core vesicles appear both in the axon terminals and in the postsynaptic area. Collateral sprouting of terminal axons with the formation of new immature junctions is observed. After 35 days of TP administration depletion of synaptic vesicles continues. Glycogen β-particles, mostly freely dispersed, occasionally seen in axon terminals 7 days after TP administration, subsequently increase in number. In the endplate zone of the muscle fibre increased protein synthesis is indicated by a rapid increase in ribosomes and irregularly located myofilaments and myofibrils. The appearance of n.m.j. after testosterone administration resembles that described after nerve stimulation; the degree of change is however less pronounced.
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  • 78
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    Cell & tissue research 189 (1978), S. 277-286 
    ISSN: 1432-0878
    Keywords: Maternal adrenalectomy ; Rat ; Influence on the adrenals of newborn animals ; Electron microscopy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Summary Maternal adrenalectomy at 7 or 14 days of gestation produced increased cell necrosis within zona reticularis cells on the day of birth and at 24 or 48 h after birth. Small remnants or large portions of adrenocortical cells were present within macrophages. In otherwise normal adrenocortical cells, lipid droplets were incorporated within some mitochondria. Autophagocytosis of single mitochondria was observed within adrenocortical cells. Undoubtedly ultrastructural changes represent stimulation of adrenocortical cells in neonatal rats in response to maternal adrenalectomy.
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  • 79
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    Cell & tissue research 191 (1978), S. 501-506 
    ISSN: 1432-0878
    Keywords: Neurohypophysis ; Ultrastructure ; Perivascular space ; Hormonerelease ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Summary Neural lobes from rats subjected to neurohypophysial hormone-releasing stimuli were examined electron microscopically following fixation in 4 % tannic acid in 2.5 % glutaraldehyde. This fixation allowed the delineation of the perivascular space in the neural lobe tissue. Measurement of the area of the perivascular space showed that it was significantly increased in the rats subjected to vagal stimulation and intraarterial calcium ions compared to the control rats. The rats which had been subjected to haemorrhage as a hormonereleasing stimulus did not show any significant change in the area of the perivascular space. The significance of these findings in relation to hormone release is discussed.
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  • 80
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    Cell & tissue research 191 (1978), S. 507-512 
    ISSN: 1432-0878
    Keywords: Odontoblasts ; Osteoblasts ; Cementoblasts ; Intercellular attachments ; Electron microscopy (SEM/TEM) ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Summary Osteoblasts of the young rat cranium, and cementoblasts and odontoblasts of young rat molars were prepared by ethanol freeze-fracture prior to critical point drying for scanning electron microscopy (SEM) as well as conventional transmission electron microscopy (TEM) techniques. Critical point drying causes shrinkage which separates the lateral intercellular contacts between neighbours in the same sheet in the case of cementoblasts and osteoblasts, but not those between odontoblasts. These differences are considered to be of functional significance and need to be taken into consideration when formulating theories of calcium influx into the mineralizable matrix of the respective tissues.
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  • 81
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    Cell & tissue research 191 (1978), S. 513-523 
    ISSN: 1432-0878
    Keywords: Median eminence ; Rat ; Freeze-fracture
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Summary Nerve terminals in the palisade zone of the rat median eminence were investigated with freeze-fracture electron microscopy. Fracture face P of the specific terminals showed two populations of intramembranous particles (IMP): a large and a small variety. The large IMP-s often formed small irregular clusters. In nerve terminals the total number of both populations of IMP-s was considerably less than that found on P membrane faces of ependymal feet. On fracture face E of the nerve terminals, the number of IMP-s was about a quarter of that seen on fracture face P. On both fracture faces of most terminals a few small round impressions (or elevations respectively) were found which may be interpreted as broken necks of either exo- or endocytotic vesicles. Neither gap nor tight junctions occurred at lateral membranes of the specific axon terminals. Similarly, no membrane specializations were observed with freeze-fracturing on membrane areas adjacent to the basement membrane. The findings are discussed in relation to a possible exocytosis mechanism of the hypothalamic releasing and inhibiting hormones.
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  • 82
    ISSN: 1432-0878
    Keywords: Taste buds ; Circumvallate papillae ; Colchicine ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Summary It is believed that differentiation and maintenance of taste buds in vertebrates is dependent on the trophic function of their sensory nerve supply. In the present work colchicine was injected into the circumvallate papilla of the rat. This produced a reversible blockade of neuroplasmic transport and disappearance of taste buds. Colchicine inhibited the further differentiation of bud cells, but apparently did not change the life cycle of the cells present already at the time of injection. It is speculated that the neurotrophic factors in this particular cell system are effective to induce cell differentiation only.
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  • 83
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    Cell & tissue research 188 (1978), S. 345-359 
    ISSN: 1432-0878
    Keywords: Hippocampal subfields ; Rat ; Volumes ; Timm stain
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Summary The absolute volumes of the hippocampal and subicular cortical layers in the rat were determined. The boundaries of the various layers were defined on series of sections made through the entire hippocampal region of five rats and stained according to the Timm sulfide silver technique. Coordinates representing the boundaries of the layers on selected sections were fed into a mini-computer programmed to calculate the volume of the layers from the areas of the profiles and the distances between the sections. The distribution of the layers indicates that they constitute the same proportion of the volume of the dorsal and ventral divisions of the hippocampal region, with the exception of the structures lying in regio inferior and regio superior. Although the combined regio superior and regio inferior components of the layers of Ammon's horn occupy the same percentage of the volume of the dorsal and ventral hippocampal regions, the regio superior components occupy a larger percentage of Ammon's horn in the dorsal region than they do in the ventral region. The inter-animal variations in the volumes of the various layers indicate that it is possible to describe quantitatively the subdivisions of the hippocampal region with a precision that is compatible with comparative studies.
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  • 84
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    Cell & tissue research 188 (1978), S. 491-496 
    ISSN: 1432-0878
    Keywords: Castration ; LH-cells ; Rat ; Development ; Sex-steroids
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Summary The effects of sex-steroids on the LH-cell development in neonatal rats were studied. The cells were stained immunohistochemically by applying anti-HCG serum. On the second day after birth some of the animals of both sexes were gonadectomized and simultaneously injected with testosterone or estradiol (50 or 200 μg). The remaining animals were either gonadectomized or injected with either one of the sex-steroids. The LH-cell numbers in each group were determined on the 12th day of age from serially cut histological sections of the pituitary. In castrated males the number of LH-cells was about twice that of the intact animals. In the so-called sex-zone, LH-cells tended to be hypertrophied in castrates. These alterations in the appearance of LH-cells did not occur after ovariectomy. In gonadectomized animals injected with sexsteroids (200 μg), the cells were markedly reduced in number and size, both in males and females. Testosterone injection (50 μg) into intact newborn animals also suppressed the numerical development of LH-cells, especially in females. These alterations were particularly evident in the sex-zone in both sexes. Thus the present findings show that sex-steroids may be involved in sexual differences in morphological development of LH-cells in newborn rats.
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  • 85
    ISSN: 1432-0878
    Keywords: Adrenal gland ; Rat ; Vinblastine ; Corticosterone ; Exocytosis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Summary Vinblastine treatment blocks corticosterone release from rat adrenal zona fasciculata without impairing hormone synthesis, and induces the formation of acid phosphatase-positive granular clumps at the juxta-sinusoidal pole of the cells. Autoradiography shows that ACTH administration to vinblastine-treated animals mobilizes the 3H-cholesterol stored in the lipid droplets and leads to a noticeable labelling of the granular clumps. The possible significance of these granules is discussed.
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  • 86
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    Cell & tissue research 188 (1978), S. 285-297 
    ISSN: 1432-0878
    Keywords: Pineal gland ; Rat ; Organ culture ; Indole metabolism ; Ultrastructural morphology
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Summary In vitro indole metabolism and ultrastructural morphology of the pineal gland of male rats were examined. A comparison of the effect of norepinephrine stimulation on indole synthesis in whole cultured glands and preparations of dispersed pineal cells is discussed. Our studies on the performance of dispersed cells during the first 24 h after preparation indicate a strong dependence of pineal cells upon physical attachment to the culture dish and probably also on cell-to-cell contact.
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  • 87
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    Cell & tissue research 192 (1978), S. 285-297 
    ISSN: 1432-0878
    Keywords: Intestinal epithelium ; Rat ; Kinetics ; Autonomic denervation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Summary The effect of autonomic denervation upon the kinetics of the ileal epithelium of rats was studied by tracing 3H-thymidine labelled nuclei and counting mitotic figures and goblet cells. Counts of labelled nuclei and goblet cells provided information about cell migration along the intestinal epithelium. The mitotic index and turnover time of this population were calculated from the mitotic figures counts. Comparing denervated animals with sham operated controls, it was possible to conclude that autonomic denervation, either sympathectomy or parasympathectomy results in a decrease in mitotic activity. As a result of lower mitotic activity in the crypts, the turnover time increases and there is a delay in the migration of cells from the crypts towards the villi. Sympathectomy causes an early short-lived effect upon the kinetics of the crypt cell population, since after 27 h there is a tendency to normality. Parasympathectomy produces a slower but continuous decline in mitotic activity.
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  • 88
    ISSN: 1439-6327
    Keywords: Exercise ; Altitude ; Left ventricular work ; Myocardial blood flow ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Total hemodynamic values and left ventricular blood flow were studied using Sapirstein's method of 86Rb uptake in female rats 24 h after a last exposure to high altitude. A simulated altitude of 1350 m was used, initial exposure being for 30 min, gradually increased by 30 min daily up to 330 min daily for 5 days a week; the total number of exposures was 32. In another animal group the hypobaric exposure was combined with swimming in water at 37
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  • 89
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    Journal of pharmacokinetics and pharmacodynamics 6 (1978), S. 505-519 
    ISSN: 1573-8744
    Keywords: morphine ; first-pass elimination ; pharmacokinetics ; enterohepatic recirculation ; availability ; routes of administration
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Morphine was administered to rats by oral, intraportal, and intravenous routes in a dose of 7.6 mg · kg −1.From the serum concentration data after intraportal administration it was calculated that the first-pass elimination of morphine in the liver amounts to 72±2% (sd). The first-pass fraction eliminated after oral administration was 85±7% (sd), thus yielding a contribution by the gut mucosa of 46% to the overall first-pass elimination after an oral dose. The results were obtained with a general compartmental model which included the kinetics of enterohepatic recirculation. The oral availability was also estimated with the aid of pharmacological effect data. This availability was in good agreement with the corresponding value determined from the serum concentration data. The results suggest that morphine is subjected to enterohepatic recirculation and that the slowest phase of decline of morphine concentrations in serum might be due to this physiological process.
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  • 90
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    Journal of pharmacokinetics and pharmacodynamics 6 (1978), S. 265-282 
    ISSN: 1573-8744
    Keywords: pharmacokinetics ; linear systems analysis ; in vivo dissolution rates ; absorption rates ; metabolic rates ; bioavailability ; numerical desconvolution
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The application of certain aspects of linear systems analysis to pharmacokinetic-problems is described. Topics covered include the evaluation of in vivodissolution rates, absorption rates, and metabolic rates, and the use of pharmacological data. Relevant numerical procedures are also discussed.
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  • 91
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    Journal of pharmacokinetics and pharmacodynamics 6 (1978), S. 315-325 
    ISSN: 1573-8744
    Keywords: percutaneous penetration ; methotrexate ; compartmental models ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Compartmental models were developed to describe the penetration of a drug from a topically applied vehicle through the skin. Data for in vitro penetration of methotrexate through hairless mouse skin from vehicles varying in PH from 3.5 to 6.5 were computer- fitted to estimate model parameters. Comparison of lag time and the exponential coefficient suggested that parallel penetration pathways exist. The fraction of drug penetrating through the shunt pathway increased as vehicle pH and ionization increased. Penetration curves were quantitatively partitioned into bulk tissue and shunt contributions. At pH 6.5, flux through the shunt pathway predominated.
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  • 92
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    Journal of pharmacokinetics and pharmacodynamics 6 (1978), S. 521-537 
    ISSN: 1573-8744
    Keywords: compartmental analysis ; doxantrazole ; drug distribution ; mathematical prediction ; pharmacokinetics ; rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract A pharmacokinetic model incorporating 14 compartments and 29 transfer coefficients has been developed from experimental data obtained after intravenous administration of a single dose to describe the distribution of doxantrazole in the rat. The distribution calculated from the model agreed closely with that determined experimentally. In addition, the model was able to predict with considerable accuracy the distribution of doxantrazole after repeated dosing.
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  • 93
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    Journal of pharmacokinetics and pharmacodynamics 6 (1978), S. 187-196 
    ISSN: 1573-8744
    Keywords: Chlorpromazine ; pharmacokinetics ; oral absorption ; single dose
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract A single oral dose (120 mg/m2) of Chlorpromazine hydrochloride was administered to four healthy subjects and the blood levels of Chlorpromazine were determined with time. Appropriate equations describing the two-compartment open model with zero-order absorption and the two-compartment model with first-order absorption, both with a lag time, were fitted to the observed data using weighted nonlinear least-squares regression analysis. Fitting the two-compartment model with zero-order absorption and a lag time to the observed data resulted in a significant reduction of the weighted sum of squared deviations, i.e., better correlation between the observed and calculated data, and a closer random scatter of the observed concentration data around the calculated curve with no apparent systematic deviations from the curve. These results suggest that Chlorpromazine absorption is zero order. Chlorpromazine began to appear in the systemic circulation after a mean lag time of 0.4 hr and continued to be absorbed for approximately 2.9 hr. The mean half-lives of the distribution and elimination phases were 1.63 and 17.7 hr, respectively.
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  • 94
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    Journal of pharmacokinetics and pharmacodynamics 6 (1978), S. 547-558 
    ISSN: 1573-8744
    Keywords: statistical moments ; network theory ; pharmacokinetics ; bioavailability ; deconvolution ; plasma concentration-time curve ; urinary excretion rate-time curve ; compartment models
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Statistical moments are parameters that describe the characteristics of the time courses of plasma concentration (area, mean residence time, and variance of residence time) and of the urinary excretion rate that follow administration of a single dose of a drug. The relationship between the moments of a time-course curve and pharmacokinetic profiles of drug disposition, i.e., absorption, distribution, metabolism, and excretion, is described. The moments are related to the extent and rate of bioavailability, and it is shown that they can be effectively applied to the deconvolution operation.
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  • 95
    ISSN: 1573-8744
    Keywords: trapezoidal rule ; area under the curve ; pharmacokinetics ; clearance ; bioavailability ; integration method ; sulfisoxazole
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The linear trapezoidal rule method is commonly used for the estimation of the area under the plasma level-time curve. Error analyses are performed when the method is used in first-order absorption and first-order elimination kinetics in the one-compartment system. It is found that significant underestimations and overestimations in area during the absorption phase and postabsorption phase, respectively, can occur when the method is improperly used. During the exponential postabsorption phase the relative error is only a function of the ratio (n)of the time interval over the half-life of the two plasma data points in the interval. The error from the linear trapezoidal rule method at n=0.5 is about 1%. The error increases to 15.5% and 57.1 % when nis increased to 2 and 4, respectively. It is recommended that for most absorption studies the linear trapezoidal method be used for prepeak and plateau plasma data and the logarithmic trapezoidal method for postpeak plasma data.
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  • 96
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    Journal of pharmacokinetics and pharmacodynamics 6 (1978), S. 295-303 
    ISSN: 1573-8744
    Keywords: tetracycline ; antibiotics ; Billroth-II gastrectomy ; gastrectomy ; pharmacokinetics ; bioavailability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The bioavailability of a single 250-mg oral dose of tetracycline hydroghloride was studied in seven patients following Billroth-II gastrectomy in comparison with seven control subjects matched for age and body weight. There were no significant differences between control subjects and gastrectomized patients in the apparent lag time prior to the start of absorption (23.6 vs. 22.8 min), peak serum tetracycline concentration (1.72 vs. 1.75 μg/ml), the time of attainment of peak concentrations (3.35 vs. 3.42 hr), the apparent first-order absorption half-life (1.8 vs. 1.4hr), or the apparent first-order elimination half-life (8.0 vs. 8.7hr). Completeness of tetracycline absorption, as judged by area under the 24-hr serum concentration curve, did not differ significantly between the two groups, nor did 24-hr urinary excretion of tetracycline. Thus the abnormalities of gastrointestinal structure and function produced by Billroth -II gastrectomy do not result in impairment of the rate and completeness of tetracycline absorption.
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  • 97
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    Journal of pharmacokinetics and pharmacodynamics 6 (1978), S. 369-387 
    ISSN: 1573-8744
    Keywords: pharmacokinetics ; dog ; diethyldithiocarbamate metabolite of disulfiram ; presence of methyl ester ; kinetic evaluation of prior studies
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Following the intravenous infusion of sodium diethyldithiocarbamate to dogs, the disposition kinetics of diethyldithiocarbamate (DDC), a metabolite of disulfiram, were assessed. Approximately 27% of the administered dose was S-methylated, this process exhibiting a mean first-order rate constant of 0. 0569 min−1 (t1/2=12.2 min), while the remainder was eliminated by other routes having a rate constant of 0.148 min−1 (t1/2=4.68 min). The methyl diethyldithiocarbamate (MeDDC) formed from DDC showed an elimination rate constant of 0.0141 min−1 (t1/2=49.2 min). These observations are discussed in the light of previous investigations where the presence of MeDDC has rarely been sought or reported. A few comparisons with prior studies, in which DDC or disulfiram was administered, are made by retrospective kinetic evaluation of published data. The results are discussed in relation to the duration of action of disulfiram in man.
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  • 98
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    European archives of oto-rhino-laryngology and head & neck 220 (1978), S. 201-212 
    ISSN: 1434-4726
    Keywords: Plica vocalis ; Epithelial surface ; Rat ; Extrapulmonary airway epithelium ; Scanning electron microscopy ; Stimmbänder ; Epitheliale Oberfläche ; Ratte ; Larynxepithel ; Rasterelektronenmikroskopie
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Zusammenfassung Das Stimmbandepithel ausgewachsener männlicher Albinoratten wird rasterelektronenmikroskopisch untersucht. Seine Oberflächenstruktur wird mit jener des Epithels auf der Plica ventricularis und im Recessus ventricularis verglichen. Charakteristischerweise zeigen die Zellen im Epithel über den Stimmbändern einen dichten, lückenlosen Besatz mit Mikrovilli. Die Übergänge des Stimmbandepithels in die benachbarten Larynxabschnitte wird dokumentiert. Besondere Aufmerksamkeit wird dem Auftreten von Mikroleisten auf den apikalen Zellpolen im Larynxepithel gewidmet, die bisher als charakteristische Struktur für das Stimmbandepithel gewertet wurden.
    Notes: Summary The epithelial surface of the Plica vocalis in adult male rat is studied by scanning electron microscopy. It's structure is compared with that of the plica and of the recessus ventricularis. The transition of the epithelium in the plica vocalis to the epithelium of the joining parts of the larynx is documented. Special attention is paid to the occurrence of microridges at the apical poles of epithelial cells in the larynx. Up to now microridge cells have been said to be characteristic for the plica vocalis.
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  • 99
    ISSN: 0006-3525
    Keywords: Chemistry ; Polymer and Materials Science
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: We have tested 21 different basis sets of synthetic DNA circular dichroism spectra and have slected one for use in spectral analyses of natural DNAs. This “standard” set consists of spectra of eight polymers: poly[d(A-A-T)·d(A-T-T)], poly[d(A-G-G)·d(C-C-T)], poly[d(A-T)·d(A-T)], poly[d(G-C)·d(G-C)], poly[d(A-G)·d(C-T)], poly[d(A-C)·d(G-T)], poly[d(A-T-C)·d(G-A-T)], and poly[d(A-G-C)·d(G-C-T)]. This basis set, applied according to the first-neighbor polymer procedure of Gray and Tinoco, allows a more uniformly accurate spectral analysis of six natural complex DNAs and eight (A+T)-rich satellite DNAs for base composition and first-neighbor frequencies than was previously possible. We find that spectra of poly[d(A)·d(T)] and/or poly[d(A-C-T-)·d(A-G-T)] are not generally required for good analysis results but we show in this and the following paper that these spectra are needed for the most accurate analyses of some satellite DNAs.
    Additional Material: 4 Ill.
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  • 100
    ISSN: 0006-3525
    Keywords: Chemistry ; Polymer and Materials Science
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: The interaction of counterions with a suitably long, charged oligomer appears susceptible to treatment in the context of polyelectrolyte theory by the introduction of an end-effect parameter that reflects the reduced association of counterions with the terminal regions of the oligo-ion. Use of a physically reasonable value for the end-effect parameter provides excellent agreement between theory and the experimental data of Elson, Scheffler, and Baldwin [J. Mol. Biol. 54, 401-415 (1970)] on the dependences of melting temperature on salt concentration and chain length for a series of hairpin helices formed by d(TA) oligomers. The differences in behavior expected for hairpin, dimer, and oligomer-polymer helices are discussed. The salt dependence of the end-joining equilibrium investigated for λ DNA by Wang and Davidson [Cold Spring Harbor Symp. Quant. Biol. 33, 409-415 (1968)] is treated as an oligomer-polymer interconversion. The dependence of equilibrium constant for this reaction on counterion concentration is in good agreement with that predicted by theory for an end-region totalling 24 nucleotides, the known length of the λ ends.
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