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  • 1990-1994  (1,188)
  • 1980-1984
  • 1990  (1,188)
  • Organic Chemistry  (891)
  • Rat  (174)
  • pharmacokinetics  (125)
  • Nuclear reactions
Material
Years
  • 1990-1994  (1,188)
  • 1980-1984
Year
  • 1
    Electronic Resource
    Electronic Resource
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 341 (1990), S. 510-516 
    ISSN: 1432-1912
    Keywords: Myenteric plexus ; Rat ; [3H]Acetylcholine release ; Muscarinic autoinhibition ; Reverse phase HPLC
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Myenteric plexus-longitudinal muscle strips isolated from the small intestine of rats were incubated with [3H]choline to measure the synthesis and the release of [3H]acetylcholine. To separate different radioactive compounds (acetylcholine, choline, phosphorylcholine) from both the tissue and the overflow a new method, the reverse phase HPLC, was used. The radiochromatogram following the injection of a [3H]choline-standard and a [14C]acetylcholine-standard onto the HPLC showed a clear separation of both isotopes with a recovery rate of roughly 100%. Incubation of the muscle strips with [3H]choline caused the synthesis of [3H]acetylcholine (30,000 dpm/preparation) that increased 2-fold, when the electrical field stimulation during labelling was increased from 0.2 Hz to 1 Hz. Electrical field stimulation (3 Hz, 2 min) caused an increase in tritium efflux that was abolished by the removal of extracellular calcium or by the addition of tetrodotoxin. Analysis by reverse phase HPLC of the overflow showed that the stimulated increase in tritium overflow was balanced by the enhanced release of [3H]acetylcholine, whereas the overflow of [3H]choline was not affected by the electrical field stimulation. Oxotremorine (1 μmol/l) suppressed the release of [3H]acetylcholine by 60%. Scopolamine (0.1 μmol/l) prevented this inhibition and, given alone, enhanced the release of [3H]acetylcholine by 43%. The release of [3H]acetylcholine evoked at 0.2, 2 or 20 Hz did not consistently decline at increasing frequencies. The present experiments show the synthesis and the calcium-dependent release of [3H]acetylcholine from the myenteric plexus-longitudinal muscle preparation of rats correspondingly to the same in-vitro preparation isolated from guinea-pigs. Muscarinic autoinhibition operates also in the small intestine of rats. However, some differences (frequency-dependency of [3H]acetylcholine release, spontaneous neuronal activity) are evident between both species. Reverse phase HPLC is a useful method to separate radioactive choline and acetylcholine with a high recovery rate.
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  • 2
    Electronic Resource
    Electronic Resource
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 342 (1990), S. 523-527 
    ISSN: 1432-1912
    Keywords: Acetylcholine ; Choline ; Dopaminergic agents ; Microdialysis ; Rat ; Striatum
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary In vivo microdialysis was used to study the putative inhibitory effects of dopamine on cholinergic interneurons in the striatum of conscious rats. The dopamine receptor agonists apomorphine (0.3 and 3 mg/kg, s.c.) and (±)N-0437 (1.4 mg/kg, s.c.) decreased interstitial concentrations of acetylcholine while increasing those of choline. In contrast, the dopamine receptor antagonists haloperidol (0.1 and 1 mg/kg, i.p.) and (±)sulpiride (20 mg/kg, i.p.) enhanced striatal acetylcholine output but had little effect on choline. Previously, a lack of effect of these drugs on striatal acetylcholine was reported. The main methodological difference between these studies was that the calcium concentration of the microdialysis perfusion solution was 3.4 mM in the former study versus 1.2 mM in the present experiments. The results of this study reemphasize the importance of the calcium concentration in determining the effects of drugs on central neurotransmitter release, and confirm a role of dopamine in the regulation of striatal cholinergic interneurons.
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  • 3
    ISSN: 1432-198X
    Keywords: Renal phosphate reabsorption ; Growth hormone deficiency ; Growth hormone releasing factor antagonist ; Renal development ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract It has been hypothesized that the high rate of renal phosphate (Pi) reabsorption in the immature animal is a consequence of the increased demand for Pi associated with the rapid rate of growth. Although growth hormone (GH) has been proposed to play a role in this process, investigations of the relationship between GH, growth and the renal Pi transport have been hampered by the lack of methods available to specifically alter circulating GH levels. This review summarizes the findings from recent studies using a newly developed peptidic antagonist to GH-releasing factor (GRF-AN) as a method of specifically inhibiting GH release. Systemic injection of GRF-AN was effective in suppressing the pulsatile release of GH, and in significantly attenuating the rate of growth, in both immature and adult rats. However, the inhibition of growth was associated with a reduction in net Pi retention only in immature rats, resulting in a doubling in the urinary excretion of Pi. GRF-AN treatment of immature rats lead to a decrease in the maximum tubular capacity to transport Pi-down to the level seen in adult rats. However, GRF-AN treatment did not alter renal Pi reabsorption in adult rats. We conclude that chronic administration of an antagonist to GRF in rats provides a new model of GH deficiency with which to study the interrelationships between growth, GH and other physiological systems. Furthermore, the findings suggest that the pulsatile release of GH, directly or indirectly, contributes to the high rate of renal Pi reabsorption in young, growing animals and may play a critical role in regulating Pi homeostasis during development.
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  • 4
    Electronic Resource
    Electronic Resource
    Springer
    Pediatric nephrology 4 (1990), S. 392-398 
    ISSN: 1432-198X
    Keywords: Nuclear magnetic resonance ; Phosphate metabolism ; Renal development ; Isolated perfused kidney ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract During growth, the capacity for renal phosphate (Pi) reabsorption varies as a function of Pi demand. These changes occur in the absence of changes in extracellular concentration of Pi and are also observed in renal cells cultured in defined media. These findings suggest a direct regulatory effect of intracellular Pi on its transport systems. We postulate that a low intracellular Pi concentration ([Pi]i) occurs in the developing kidney as a consequence of differences in Pi metabolism between growing and mature cells and that a low [Pi]i, in turn, leads to adaptive changes in renal Pi transport. In order to assess this hypothesis, we used31P-nuclear magnetic resonance (NMR) to measure the intracellular concentrations of NMR-visible Pi and phospho-metabolites and the rates of Pi turnover due to adenosine triphosphate (ATP) synthesis, in isolated perfused kidneys of 3- to 4-week-old and 12- to 13-week-old rats. The [Pi]i was lower (1.7±0.1 vs 2.7±0.1 mM,P〈0.05) in kidneys of growing than of adult rats, while the ATP (2.9±0.3 vs 2.8±0.5 mM) and adenosine diphosphate (ADP)(−0.2 mM) concentrations were similar at the two ages, consistent with a high phosphorylation potential in the kidneys of the younger animals. Radiofrequency irradiation of the γ-P of ATP resulted in reduction in the intensity of the Pi resonance of 62±5% in the newborn and 38±3% in the adult (P〈0.05). The corresponding 1.6-fold higher fractional turnover rate of the Pi pool in the younger than in the older rats accounts for the similar rates of ATP synthesis at the two ages (30±7 vs 35±4 μmol/min per g,P〉0.3), despite the smaller intracellular Pi pool present in the younger than in the older animals. The low [Pi]i may stimulate the synthesis of 1,25 hydroxivitamin D3 and the expression of Pi transport related proteins. The high phosphorilation potential drives the ATP flux necessary for growth related transport and biosynthetic processes.
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  • 5
    Electronic Resource
    Electronic Resource
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 342 (1990), S. 107-109 
    ISSN: 1432-1912
    Keywords: Muscarinic receptors ; Adenylate cyclase ; Olfactory bulb ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary In membranes of rat olfactory bulb acetylcholine stimulated adenylate cyclase activity in a concentration-dependent manner. The maximal stimulation corresponded to 53% increase of basal enzyme activity and was obtained with 100 μM acetylcholine. The concentration of the cholinergic agonist eliciting a half-maximal effect was 0.4 μM. The stimulatory effect of acetylcholine was antagonized by 0.1 μM atropine but not by 10 μM (+)-tubocurarine. Moreover, the addition of micromolar concentrations of GTP was absolutely required for the enzyme stimulation by acetylcholine. The results demonstrate the presence in rat olfactory bulb of muscarinic receptors coupled to stimulation of adenylate cyclase probably via a GTP regulatory protein and provide evidence for a novel signal transduction mechanism of central muscarinic receptors.
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  • 6
    ISSN: 1432-1912
    Keywords: Pharmacokinetics ; [3H]-Hexahydro-siladifenidol ; Sila-drug ; Rat ; Autoradiography
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The pharmacokinetics of tritiated hexahydrosila-difenidol ([3H]-HHSiD) were examined in rats. Furthermore, the distribution of radioactivity was studied by means of whole body autoradiography. After i. v. administration of 2.9 mg/kg HHSiD plus [3H]-HHSiD to anaesthetized rats bearing a catheter implanted in the ductus choledochus and receiving a mannitol infusion, HHSiD was rapidly distributed and metabolized. Only 5% of the radioactivity was recovered in blood after 23 s and 0.4% after 2.5 h. 64% of the plasma radioactivity could be extracted with hexane from the samples taken 23 s after administration. 52% of the radioactivity was eliminated within 2.5 h, 13% by urinary and 39% by biliary excretion. Following oral administration of 8.6 mg/kg HHSiD plus [3H]-HHSiD there was an absorption of approximately one fourth of the administered radioactivity within 4 h. By means of whole body autoradiography (i. v. injection) as well as by tissue distribution measurement the highest levels of radioactivity were found in bile, urine, lung, kidney, adrenals, liver and pancreas. Thus, after i. v. administration to rats HHSiD is rather quickly distributed, metabolized and excreted. This explains its low antimuscarinic potency in vivo.
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  • 7
    Electronic Resource
    Electronic Resource
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 342 (1990), S. 189-193 
    ISSN: 1432-1912
    Keywords: Bradykinin ; NPC 567 ; Bradykinin antagonist ; Inflammation ; Carrageenan ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Bradykinin has been implicated in acute inflammatory reactions. Intradermal injection elicits increased vascular permeability and hyperalgesia, and bioassays have suggested increased bradykinin concentration in inflammatory exudates. Poorly specific inhibitors of kallikrein, the enzyme catalyzing formation of bradykinin, inhibit certain acute inflammatory reactions. However, the lack of a specific bradykinin receptor antagonist has made proof of the hypothesis difficult. In this study, we have used the potent, specific bradykinin antagonist DArg[Hyp3DPhe7] bradykinin (NPC 567) as a probe to examine the role of bradykinin in carrageenan-induced edema in the paws of rats. Subplantar injection of carrageenan led to an increase in immunoreactive bradykinin and metabolic product, desArg9bradykinin. NPC 567 inhibited the development of edema in response to carrageenan, to a maximum 65%. Thus, bradykinin appears to be a major mediator of increased vascular permeability in response to carrageenan.
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  • 8
    Electronic Resource
    Electronic Resource
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 342 (1990), S. 719-721 
    ISSN: 1432-1912
    Keywords: Autoradiography ; Dopamine DA-1 receptors ; Kidney ; Juxtaglomerular cells ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The binding of the selective DA-1 receptor antagonist [3H]-SCH 23390 in sections of rat kidney was studied using combined in vitro biochemical radio-receptor assay and autoradiography. [3H]-SCH 23390 was bound to sections of rat kidney in a manner consistent with the labeling of DA-1 receptors with a disssociation constant value of 4.2 nmol/l and a Bmax value of 180.6 fmol/mg protein. Light microscope autoradiography revealed a dense accumulation of silver grains in juxtaglomerular cells and in proximal convoluted tubule cells. These findings suggest that the stimulation of renin release elicited by dopamine and DA-1 receptor agonists may be mediated by the activation of DA-1 receptors located on juxtaglomerular cells.
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  • 9
    Electronic Resource
    Electronic Resource
    Springer
    Journal of molecular medicine 68 (1990), S. 125-128 
    ISSN: 1432-1440
    Keywords: B-vitamins ; Spinal dorsal horn ; Afferent inhibition ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Afferent inhibition of spinal dorsal horn neuronal responses to noxious skin heating was induced by transcutaneous electrical nerve stimulation in pentobarbital-anesthetized rats. Pretreatment with B vitamins significantly enhanced this afferent inhibition, possibly due to an increase in the synthesis rate of inhibitory neurotransmitters in central neurones.
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  • 10
    Electronic Resource
    Electronic Resource
    Springer
    Journal of molecular medicine 68 (1990), S. 142-145 
    ISSN: 1432-1440
    Keywords: Pyridoxine ; B Vitamins ; CNS ; Serotonin receptor binding ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Treatment of normal adult rats with pyridoxine or a B-vitamin mixture resembling Neurobion® 1 led to an increase in serotonin content of various brain areas and to a decrease in the number of serotonin S2 receptors. The results indicate that the pyridoxal phosphate level in regions of the brain regulates the extent of decarboxylation of 5-hydroxytryptophan, the precursor of serotonin. The results also suggest a continuum from deficiency in pyridoxine to treatment of animals with a moderate excess of pyridoxine which is reflected in the synthesis and secretion into the synaptic cleft of the neurotransmitter serotonin.
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  • 11
    ISSN: 1432-0738
    Keywords: N-Nitrosomethylethylamine ; Deuterium isotope effect ; N-Nitrosomethyl(2,2,2-trideuterioethyl)amine ; Toxicokinetics ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract To investigate the origins of an organotropic shift toward increasing esophageal carcinogenicity and DNA alkylation caused by β-trideuteration of the hepatocarcinogen,N-nitrosomethylethylamine (NMEA), the single-dose toxicokinetics of NMEA andN-nitrosomethyl(2,2,2-trideuterioethyl)amine (NMEA-d 3) has been characterized in 8-week-old male Fischer 344 rats by analysis using high performance liquid chromatography of serial blood samples. An i.v. bolus dose of 0.6 μmol/kg to rats revealed biphasic first order elimination with a terminal half-life of 9.46 ± 0.69 min for unchanged NMEA and 28.9 ± 2.4 min for total radioactivity. Extensive conversion to polar metabolites was observed in the chromatograms. The systemic blood clearance and apparent steadystate volume of distribution for unchanged NMEA were 39.9 ± 4.6 ml/min/kg and 496 ± 36 ml/kg, respectively. There was negligible plasma protein binding and no detectable NMEA was excreted unchanged in the urine. Larger doses given by gavage indicated a systemic bioavailability of 25 ± 1%. Similar doses of NMEA-d 3 given to other groups of rats revealed no significant differences in any of the toxicokinetic parameters. NoN-nitrosomethyl (2-hydroxyethyl)amine was found as a detectable metabolite of NMEA or NMEA-d 3 in any of the blood or urine samples which were analyzed. When considered together, the data suggest that previously observed differences in organ specificity for the carcinogens, NMEA and NMEA-d 3, are not due to differences in the total amounts of nitrosamine reaching particular tissues, but may have other localized causes such as differences in the enzymes responsible for metabolism which are present in each tissue. Such differences may make too small a contribution to the total systemic clearance to be detectable in that parameter, but at the level of the fraction of a dose that alkylates DNA they may be important.
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  • 12
    ISSN: 1432-0738
    Keywords: Fly ash ; Metals ; Distribution ; Organs ; Rat ; Fetus
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Fly ash (100 mg/kg body weight) was administered intratracheally to 14-day pregnant rats for 6 consecutive days. On day 20 of gestation the translocation of metals present in the fly ash to various maternal and fetal organs was studied. Fly ash administration to pregnant mothers retarded the growth of fetal heart and kidney as determined by their weights. Fly ash instillation increased organ levels of nearly all the metals studied in both mother and fetus. Most of the metals present in coal fly ash were transferred in significant amounts through placenta to several fetal organs. However, the pattern of their distribution into various fetal organs was different for different metals.
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  • 13
    ISSN: 1432-0738
    Keywords: Gasoline ; Rat ; Liver ; Microsomal mono- oxygenase activity
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Previous work has shown an increase in rat liver enzyme activities after chronic exposure to gasoline vapor. In the present study, male Sprague-Dawley rats were pretreated with unleaded gasoline at 1 and 5 ml/kg, i.p., and selected hepatic microsomal monooxygenase activities were determined at 18, 48, and 72 h. At 18 h, moderate increases were observed in P450 content (1.3-fold), cytochromec-reductase activity (1.25-fold), and inN-nitrosodimethylamine demethylation rate (1.25- to 1.6-fold). Pentoxyresorufin dealkylase activity (an activity displayed primarily by P450IIB1) was significantly elevated at 18 and 48 h (30- to 60-fold), and ethoxyresorufin dealkylase activity (an activity displayed by P450 IA1) was elevated (2- to 4-fold). Immunoblot analysis revealed no change in P450IIE1 at these time points, but an elevation in P450IIB1 in agreement with the pentoxyresorufin dealkylase activity measurements.
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  • 14
    ISSN: 1432-0533
    Keywords: Focal cerebral ischemia ; Middle cerebral artery ; Rat ; Reperfusion ; 2,3,5-Triphenyl-tetrazolium chloride
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The extent of histochemical change following middle cerebral artery occlusion was quantitatively determined in three groups of Sprague-Dawley rats with 2,3,5-triphenyltetrazolium chloride (a marker of mitochondrial oxidative enzyme function). In group I (n=7) occlusion was maintained for 3 h, with immediate sacrifice. In group II (n=7) occlusion was maintained for 5 h, with immediate sacrifice. In group III (n=7) occlusion was maintained for 3 h, followed by a 2-h period of reperfusion prior to sacrifice. The area of injury was significantly larger (P〈0.05) in the 5-h occlusion group [15±4% (mean±SD)] compared to the 3-h occlusion group (9±2%); indicating a time-dependent worsening of the histochemical detection of injury. However, the area of injury was significantly less in the reperfusion group (5±2%) compared to the group that was evaluated after 3 h of occlusion without reperfusion (9±2%); indicating that some component of the injury revealed by 2,3,5-triphenyltetrazolium chloride is potentially reversible. These data suggest that contrary to previous understanding, the histochemical abnormality revealed by 2,3,5-triphenyltetrazolium chloride is reversible in some circumstances and does not necessarily represent inevitable infarction.
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  • 15
    ISSN: 1432-0568
    Keywords: Creatine kinase ; Development ; Distribution ; Rat ; Heart ; Muscle ; Immunohistochemistry
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The distribution pattern of creatine kinase (E.C 2.7.3.2) isozymes in prenatal rat heart and skeletal muscle was studied by immunohistochemistry. Between embryonic day (ED) 12–18, creatine kinase M (CK-M) is heterogeneously expressed in the heart: a pronounced staining of CK-M is first observed in the outflow tract and the trabeculae of the right ventricle (ED12-14), and subsequently in the venous valves, the interatrial septum and the sinoatrial node. From ED18 onwards, a homogeneous expression of CK-M is observed due to an increase in isozyme concentration in the remaining part of the myocardium. By contrast, the developmental appearance of creatine kinase B (CK-B) occurs almost homogeneously throughout the heart between ED11-14. Thereafter, a decrease of the CK-B is first observed in the inflow tract (in particular in the sinoatrial node), in the inner part of those atrial walls that are adjacent to the atrioventricular junction, and temporarily in a band in the upper part of the interventricular septum. From ED18, a selective disappearance of CK-B is found in the papillary muscle of the left ventricle. At birth, a considerable amount of CK-B remains present in the ventricular walls. Although some of the stage-dependent regional differences in expression of the creatine kinase isozymes, in particular those of the M-subunit, are shared by other mammalian and avian species, their significance for the developmental changes in the physiology of the heart is speculative at present.
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  • 16
    ISSN: 1432-0568
    Keywords: Basket cells ; Hippocampus ; Dentate gyrus ; Rat ; Postnatal development
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Light and electron microscopic preparations were used to analyze the postnatal development of the basket cells of the rat dentate gyrus. The basket cells, located at the hilar border, were recognized in 2-day-old rats in Golgi preparations, where they displayed immature dendrites and a small axon arbor in the granule cell layer. At 5 days, the basket cells were found to have a large perikaryal cytoplasm, a round nucleus, an axon that forms symmetric synapses with granule cells, and dendrites and somata that are contacted by other axon terminals. The 10-day basket cells display more mature features, such as Nissl bodies and well-developed Golgi complexes. The basket cells from 16-day-old rats are mature in terms of their ultrastructural features, in that the nuclei are highly indented and display intranuclear rods or sheets, the perikaryal cytoplasm is packed with organelles, and the axon has developed an extensive arborization with the somata and dendrites of granule cells at the border with the molecular layer. This arborization will continue to expand as more granule cells are generated and added to the hilar border. These data correlate well with the immunocytochemical and biochemical development of GABAergic neurons in the dentate gyrus. Furthermore, the maturation of the structure of basket cells appears to precede the appearance of adult-like electrical activity in the hippocampus.
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  • 17
    Electronic Resource
    Electronic Resource
    Springer
    Cellular and molecular life sciences 46 (1990), S. 457-458 
    ISSN: 1420-9071
    Keywords: Rat ; carnitine ; lipolysis ; exercise ; glycogen ; triglycerides ; muscle
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Summary To test the effect of L-carnitine on glycogen sparing when fat oxidation is increased, 100 mg/kg/d were given to rats orally for 3 days, resulting in 1.8-fold higher muscle carnitine levels. Even when FFA were raised by heparin-stimulated lipolysis, the rate of glycogen degradation was not reduced during exercise.
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  • 18
    ISSN: 1432-0533
    Keywords: Rat ; Mongolian gerbil ; Trimethyltin ; Dense bodies ; Golgi appratus
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The different responses of neurons with distinctive variations in morphology and function, confirm earlier observations of the lack of uniformity in the reaction of nerve cells to trimethyltin. Thus, hippocampal pyramidal and cortical neurons in both rat and Mongolian gerbil (M. unguiculatus) show abundant lysosomal dense bodies and disorganisation of the protein-synthesising apparatus. Cerebellar Purkinje cells in gerbil, but not in rat, show striking increases in smooth membrane systems, while dense bodies are insignificant in both species; large motor-type neurons in brain stem and spinal cord in both species do not accumulate dense bodies, but their rough endoplasmic reticulum (RER) may undergo intense vacuolation with or without subsequent cell death; and by contrast, spinal ganglion cells of both species may form an excess of dense bodies and, in the gerbil, vacuolation of RER. In contrast with these varied responses to trimethyltin most neurons, large and small, in both species regularly undergo striking vacuolation of the Golgi apparatus in the earliest phase of the intoxication, a constant feature that probably reflects the site of the primary cytotoxic lesion; all other changes we consider are secondary to such damage to the Golgi apparatus, however this may come about. These observations are discussed in relation to earlier reports of the variable effects of trimethyltin and with the metabolic changes reported in trimethyltin intoxication that in general accord with these morphological conclusions.
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  • 19
    Electronic Resource
    Electronic Resource
    Springer
    Anatomy and embryology 182 (1990), S. 225-234 
    ISSN: 1432-0568
    Keywords: Cranial veins ; Basal drainage ; Development ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The anatomical pattern and development of the venous system of the cranial base in the rat is described. The anatomy of the venous system was determined from observations of vascular casts in adult ratss; the development of the vascular system was established by examination of ink-injected embryos. A transverse sinus system was found to be present in the basal venous system. The sinus connects the posterior facial veins; its middle section transverses the cranial base through the basisphenoid canal, and it receives the venae ophthalmicae within the basisphenoid bone. The venae ophthalmicae in turn are connected to the perioptic veins and to the sinus interperiopticus intracranially. Dorsally, the venae ophthalmicae anastomose with the paired sinus cavernosus. The term sinus transversus basalis is proposed for the venous connection between the posterior facial veins within the basisphenoid bone of the rat. The anlage of the sinus transversus basalis is established by vascular networks during the final prenatal period, its formation, however, is only completed postnatally. The anlages of the venae periopticae, the venae ophthalmicae, the sinus cavernosus and the rami intercavernosi are already established at early developmental stages. The characteristic pattern is formed before birth.
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  • 20
    Electronic Resource
    Electronic Resource
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    Anatomy and embryology 182 (1990), S. 307-317 
    ISSN: 1432-0568
    Keywords: Rat ; Kidney ; Interstitial cells ; Major histocompatibility complex
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary To study the ontogenetic development of the interstitial tissue of the kidney, rats were investigated 1, 3, 7, 14, 21 and 28 days after birth. Kidneys perfusionfixed with glutaraldehyde were studied with light- and electron microscopy. Cryostate sections from kidneys immediately frozen in liquid nitrogen were studied with respect to the expression of MHC class II antigen using the monoclonal antibody OX6. The interstitial space of both the renal cortex and the outer and inner medulla was prominent during the first days postnatally. The relative interstitital volume of the cortex and outer part of the medulla then decreased in conjunction with the outgrowth and maturation of the superficial nephrons while the inner medullary interstitium remained wide. During the first postnatal days, the abundant interstitial cells of the cortex were connected via cytoplasmic processes to form a loose network which later became less well defined. The lipid-laden interstitial cells of the inner medulla showed essentially the same ultrastructure in the newborn as in the adult animal. Strong expression of class II antigen first appeared on epithelial cells of the thick ascending limb of Henle’s loop about 7 days postnatally, and became weak at 28 days. From 21 days, a weak staining of the proximal tubules was also observed. While interstitial cells in the inner medulla were always negative, cortical and outer medullary interstitial cells became strongly positive for class II antigen from day 21 post partum.
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  • 21
    Electronic Resource
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    Springer
    Anatomy and embryology 181 (1990), S. 441-452 
    ISSN: 1432-0568
    Keywords: Development ; Pancreatic primordium ; Transplantation ; Immunohistochemistry ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The dorsal pancreatic primordia of 12.5-day-old rat embryos transplanted into the third ventricle of adult female rats were immunohistochemically examined 10, 20 and 40 days after transplantation. On day 10, the grafts grew into an epithelial sacculus (S) with a thick subepithelial tissue (ST). Tubular and vesicular structures with a single cuboidal epithelium were found within the wall of the S, but they underwent thereafter a regression without allowing the primordia to differentiate into the exocrine acinar tissues. In contrast with this, pancreatic hormone-containing cells existed in the ST, and were arranged like the islands of a mature animal. The tissue also has smooth muscle fibers and neurons. When the primordium was grafted along with its root connected to the duodenum, gut-like tubular structures differentiated, showing mucosa with villi and crypts, submucous mesenchymal tissue and muscle layers. The mucosa possesses epithelial cells immunoreactive for the pancreatic hormones, and the muscle layers have the myenteric plexuses. These findings seem to provide further evidence that in the rat pancreas, pancreatic-hormone-containing cells differ from the acinar cells in origin.
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  • 22
    Electronic Resource
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    Springer
    Anatomy and embryology 181 (1990), S. 603-614 
    ISSN: 1432-0568
    Keywords: Neocortex ; Rat ; 2-deoxyglucose ; Local cerebral glucose utilization ; Laminar pattern ; Image analysis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The neocortex of the rat brain can be subdivided into regions of different local cerebral glucose utilization (LCGU). However, only a few neocortical areas can be delineated by differences in mean LCGUs between neighbouring areas. These area borders correspond exactly with cytoarchitectonically defined borders found in adjacent Nissl-stained preparations. On the other hand, nearly all of the architectonically defined area borders are also recognizable in the LCGU pictures, if differences in laminar distribution patterns of LCGU are taken into account. Furthermore, interareal differences in mean LCGU mainly reflect changes in layer IV, whereas layers II–III and V–VI show nearly identical LCGU values in all neocortical areas of the rat brain. The primary sensory areas exhibit the highest LCGU in layer IV, while the primary motor cortex shows a high LCGU in layer V. As the cytoarchitectonically defined pattern of the cortex is generally corroborated by the regional and laminar LCGU distribution, anatomical, metabolic and functional aspects of cortical architecture are associated.
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  • 23
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    European journal of clinical pharmacology 38 (1990), S. 175-179 
    ISSN: 1432-1041
    Keywords: diflunisal ; smoking ; pharmacokinetics ; sex-differences ; oral contraceptive steroids
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The single dose pharmacokinetics of diflunisal were studied in 4 groups of 6 young volunteers: control men, control women, women taking low estrogen oral contraceptive steroids (OCS), and women smokers (10–20 cigarettes/day). The plasma clearance of diflunisal was significantly higher in men (0.169 ml·min−1·kg−1) and in women on OCS (0.165 ml·min−1·kg−1) as compared to control women (0.108 ml·min−1·kg−1). Partial metabolic clearances of diflunisal by the three conjugative pathways (phenolic and acyl glucuronide formation, sulphate conjugation) were all increased in men and women OCS users as compared to control women. Statistically significant increases, however, were only observed for the partial metabolic clearance of diflunisal by phenolic glucuronidation between men and women (2.91 vs. 1.85 ml·min−1 respectively), and for the partial clearance by acyl glucuronidation between OCS users and control women (4.81 vs. 3.01 ml·min−1 respectively). Smoking resulted in a moderate increase (35%) in plasma diflunisal clearance. However, a significant reduction in total urinary recovery of diflunisal and its glucuronide and sulphate conjugates was found in smokers (70.5% in smokers as compared to 84.2–87.2% in the 3 other study groups). Consequently, smoking may have induced hydroxylation, a minor oxidative metabolic pathway of diflunisal recently discovered in man.
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  • 24
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    European journal of clinical pharmacology 38 (1990), S. 181-184 
    ISSN: 1432-1041
    Keywords: cyclosporin A ; diabetic children ; pharmacokinetics ; dose adjustment
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Cyclosporin A (CsA) pharmacokinetics was studied in 19 diabetic children (mean age: 10.6 y). They were divided into prepubertal (I) and pubertal (II) groups according to plasma oestradiol or testosterone concentrations. The kinetic study was performed after a 72 h wash out period and a single oral dose of 7.5 mg/kg CsA. CsA in blood was measured by HPLC. The kinetic parameters: Cmax, tmax, t1/2, AUC, CL/f, Vz/f and tss were calculated. No significant difference was found between the two groups. A significant negative correlation was found between Vz and both total cholesterol (r=0.46), VLDL+LDL−cholesterol (r=−0.49) and VLDL+LDL−phospholipids (r=−0.58). CsA kinetics at steady-state were simulated by superimposition of single dose kinetics derived from each single dose. Measured steady-state blood concentrations were correlated (r=0.80) with the values predicted by the simulation. The results suggest that CsA adjustment dosage of the CsA may be performed after a single oral dose using blood levels measured by HPLC. This procedure requires validation in further studies.
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  • 25
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    European journal of clinical pharmacology 38 (1990), S. 189-193 
    ISSN: 1432-1041
    Keywords: estramustine phosphate ; prostatic cancer ; gastrointestinal absorption ; food intake ; calcium ; drug interaction ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effect of milk and food on the pharmacokinetics of estramustine phosphate was investigated in six patients with prostatic cancer. In a randomized three-way cross-over study, the patients were given single doses of the drug together with low calcium water, low calcium food and milk. The evaluation was based upon the plasma concentration of two metabolites, estromustine and estrone, as parent drug could not be detected in plasma. The tmax and lag time of estromustine were significantly increased by milk and food intake and Cmax and AUC were significantly decreased. In comparison with water, the AUC of estromustine was 41% when the drug was taken with milk and 67% after simultaneous intake of standardized food. Corresponding figures for the peak values were 32 and 57%, respectively. The effect of milk and food intake on the pharmacokinetics of estrone was similar. Studies in vitro demonstrated that the dissolution of estramustine phosphate disodium was markedly impaired in the presence of calcium. It was concluded that the rate and extent of absorption of estramustine phosphate were decreased when the drug was taken with milk or food due to the formation of a poorly absorbable calcium complex. To obtain high and reproducible absorption of Estracyt®, the drug should not be taken together with milk, milk products or other calcium-rich food or drugs.
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  • 26
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    European journal of clinical pharmacology 39 (1990), S. 165-167 
    ISSN: 1432-1041
    Keywords: Cyclosporin A ; ponsinomycin ; pharmacokinetics ; drug interaction ; macrolide antibiotic ; renal transplantation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The influence of treatment with ponsinomycin, a new macrolide antibiotic, on the pharmacokinetics of cyclosporin A has been studied in 10 renal transplant patients. The pharmacokinetics of cyclosporin A was investigated at steady state, before and during treatment with ponsinomycin. On average, the blood levels of cyclosporin A were doubled by the macrolide, possibly due to a decrease in elimination or/and to an increase in absorption. Ponsinomycin should be use very carefully in patients treated with cyclosporin A.
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  • 27
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    European journal of clinical pharmacology 39 (1990), S. 189-190 
    ISSN: 1432-1041
    Keywords: Diltiazem ; bioinequivalence ; plasma concentration ; dissolution ; pharmacokinetics ; commercial brands
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary A bioequivalence study of three brands of regular diltiazem — Angizem (A), Dilzem (B) and Herbesser (C) has been carried out in 5 healthy, male volunteers. After a single oral dose of 60 mg of each preparation, the mean AUC(0–8 h) and Cmax of preparation B was significantly higher than of brands A and C. The tmax of A and B was significantly lower than of C. B had a higher dissolution rate in vitro (98.8% dissolved in 45 min) than A and C. Thus, there was bioinequivalence of the three brands of diltiazem, due partly to differences in dissolution and perhaps in part to a first pass effect.
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  • 28
    ISSN: 1432-1041
    Keywords: Flurbiprofen ; sustained-release formulation ; tolerance ; pharmacokinetics ; adverse reaction
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetic profile of 200 mg sustained-release flurbiprofen capsules was compared in nine elderly (mean age 84.2 years) and 10 young (mean age 38.1 years) patients with arthritis. After a single capsule, a 48 h plasma concentration profile was performed. The patients then took 1 capsule daily for a further 13 days with plasma levels of the drug being measured pre-dose on alternate days. Following ingestion of the last capsule, a further 48 hour plasma concentration profile was performed. These results were compared with each other and with computer predicted data obtained from dosing with 200 mg conventional flurbiprofen (as 100 mg b.d.). In both young and elderly patients, the two 48 h plasma concentration profiles confirmed the sustained-release characteristics of the capsule. There was no evidence of dose-dumping, although, in one elderly patient with a partial gastrectomy, higher plasma concentrations were observed. Inter- and intra-patient variability was acceptable. A steady-state was achieved within the predicted four days in both groups and there was no evidence of accumulation with the daily dosing interval. A mean steady-state level of approximately 6 μg/ml was achieved for both populations. Computer predicted data for 200 mg conventional flurbiprofen (as 100 mg b.d.) showed a pre-dose/peak range of 1–12 μg/ml. The pre-dose/peak ranges for the young and old patients were 4–10 μg/ml and 4–8 μg/ml respectively. One young patient developed a hypersensitivity reaction of moderate severity; one young and four elderly patients developed a low haemoglobin concentration during the study. No other changes in haematological or biochemical parameters were seen.
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  • 29
    ISSN: 1432-1041
    Keywords: metoprolol ; oral osmotic drug delivery system (OROS) ; food intake ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The influence of food intake on the bioavailability of metoprolol from an OROS system has been investigated. No significant difference was found between OROS administration to fasting subjects or after breakfast in any of the kinetic parameters (AUC, Cmax, tmax, C24 and lag time). Therefore, metoprolol OROS can be administered with breakfast.
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  • 30
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    European journal of clinical pharmacology 39 (1990), S. 385-389 
    ISSN: 1432-1041
    Keywords: Levodopa ; Parkinson's disease ; pharmacokinetics ; pharmacodynamics ; modeling
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Five patients with severe Parkinson's disease were characterized with respect to their pharmacokinetic and pharmacodynamic responses to levodopa given: orally, intravenously (three different infusion rates) and intraduodenally. The best therapeutic infusion rate in the intravenous study was used for the intraduodenal infusion of levodopa. A lag time between plasma concentration and effect following oral administration was seen in three of the five patients and this disequilibrium was estimated as the rate constant ke0 using model-independent analysis. The plasma concentration-effect relationship was similar for the three modes of administration and in all patients the therapeutic plasma concentration for full mobility was 〉4–5 μg·ml−1. The disequilibrium half-life for development of effect after oral administration was calculated to be about 30 min. The patients remained clinically stable during the period of the intraduodenal infusion.
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  • 31
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    European journal of clinical pharmacology 39 (1990), S. 395-397 
    ISSN: 1432-1041
    Keywords: atropine ; exercise ; pharmacokinetics ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Seven healthy males (19–32 y) underwent each of four separate conditions in a repeated measures design. Five of these subjects underwent an additional trial. In four of five trials subjects received 2.0 mg atropine sulfate intramuscularly in the anterolateral portion of the left thigh: at rest (T1); following completion of a single exercise (Ex) bout (T2), (Each bout consisted of 25 min of stationary cycling at 40% VO2 max with 5 min of seated rest), prior to three Ex bouts (T3) and following one and prior to three Ex bouts (T5). Trial 4 (T4) was the same as T3 with the substitution of a saline placebo. Serum samples were collected over a 12 h period and atropine concentration was determined by RIA. Ex trials were compared to T1. Ex prior to atropine (T2) significantly decreased the mean volume of distribution (Vz, 278 vs 2321). Ex in T3 significantly decreased the serum half life (t1/2, 4.2 vs 3.5 h), Vz (278 vs 1981), and clearance (CL, 763 vs 638 ml·min−1) and significantly increased the peak concentration (Cp, 6.7 vs 12.3 ng·ml−1) and area under the curve (AUC, 44.1 vs 53.1 ng·ml−1). In T5, Ex significantly decreased the t1/2 (3.4 h), Vz (182 l) and CL (575 ml·min−1) and significantly increased the absorption rate constant (ka, 0.482 vs 1.1 min−1), elimination rate constant (ke, 0.0012 vs 0.0015 min−1), Cp (14 ng·ml−1) and AUC (53.3 ng·h·ml−1). These results demonstrate that moderate Ex either prior to and/or immediately following drug administration has the capacity to significantly modify atropine pharmacokinetics.
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  • 32
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    European journal of clinical pharmacology 39 (1990), S. 507-513 
    ISSN: 1432-1041
    Keywords: Anthracyclines ; cancer patients ; iodo-doxorubicin ; doxorubicin ; pharmacokinetics ; metabolism
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of doxorubicin (DOX), iodo-doxorubicin (I-DOX) and their metabolites in plasma has been examined in five patients each receiving 50 mg/m2 of both anthracyclines as a bolus injection. Terminal half-life, mean residence time (MRT), peak plasma concentration Cmax, and area under the curve (AUC) appeared smaller for I-DOX, whereas its plasma clearance (CLp) and volume of distribution at steady state (Vss) were larger than for DOX. The major metabolite of I-DOX was iodo-doxorubicinol (I-AOL) followed by doxorubicinol aglycone (AOLON). The AUC of I-AOL was 6-times larger than that of its counterpart AOL, which is the major metabolite of DOX. AOLON generated after I-DOX administration is a further important metabolite, as its AUC was 10-times larger than that of AOLON generated from DOX. The other aglycones, such as doxorubicin aglycone (AON) and the 7-deoxy-aglycones were only minor metabolites after either I-DOX or DOX injection. The ratio AUCI-AOL/AOL/AUCI-DOX/DOX was 27 in the case of I-DOX and 0.4 after DOX. The terminal half-lives of the cytostatic metabolites I-AOL and AOL were similar, although a longer MRT for AOL was calculated. Both metabolites had much longer MRTs than their parent drugs. The MRTs of the aglycones AOLON and AON were greater than those of the 7-deoxy-aglycones after both I-DOX and DOX. Approximately 6% DOX and less than 1% I-DOX were excreted by the kidneys during the initial 48 h. About 5% of I-DOX was excreted via the kidneys as I-AOL. Aglycones were not detected in significant amounts. The plasma concentrations of all compounds measured were highest during the first few minutes after administration of I-DOX and DOX. The I-AOL concentration was comparable to that of I-DOX immediately after the injection, due to very rapid metabolism within the central compartment (vascular space) by the aldoketo reductase system in the erythrocytes. The plasma concentration-time curves of (7d)-aglycones showed a second peak between 2 and 9 h after injection, suggesting enterohepatic circulation of metabolites lacking the daunosamine sugar moiety.
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  • 33
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    European journal of clinical pharmacology 39 (1990), S. 569-572 
    ISSN: 1432-1041
    Keywords: Bopindolol ; cirrhosis ; antipyrine ; pharmacokinetics ; side effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The plasma concentration-time curve of the hydrolysis product of bopindolol has been investigated in 14 patients with cirrhosis and in 15 healthy volunteers given a single oral dose of 2 mg bopindolol. Cirrhosis was confirmed by history and clinical examination or liver biopsy. The time to maximum concentration, maximum concentration and AUC of hydrolyzed bopindolol were similar in the patients and controls. However, the elimination half-life was 6.0 h in controls and 9.5 h in cirrhotics. Antipyrine clearance was markedly decreased in patients with cirrhosis, but no correlation was found with the pharmacokinetic parameters of hydrolysed bopindolol. Although the AUC was not significantly altered in patients with cirrhosis, the longer half-life of hydrolysed bopindolol suggests impairment of its disposition in liver disease, which could lead to significant accumulation of drug during chronic dosing.
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  • 34
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    European journal of clinical pharmacology 39 (1990), S. 577-581 
    ISSN: 1432-1041
    Keywords: Benzbromarone ; elimination phenotypes ; pharmacokinetics ; metabolism ; genetic variation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Following oral administration of the uricosuric drug benzbromarone two major metabolites appear in the circulation, 1'-hydroxy-benzbromarone (M1), and a second product (M2) of unknown structure. The plasma concentrations of the parent drug and of M1 and M2 have now been compared in two different elimination phenotypes, 10 subjects who eliminated the drug rapidly (S1–10) and one individual (S11) whose elimination capacity was impaired, presumably due to genetic variation (S11). The AUC (0–96) of the parent drug in S11 was 145 gmg · ml−1 h, and in the other individuals it averaged 18.3 (11.4–24.5) μg · ml−1 h. The plasma elimination half life of benzbromarone was 3.34 (1.77–5.24) h in the rapid eliminators, and 13.08 h in the subject with the elimination defect. The mean plasma elimination half life of the metabolites in S1–10 amounted to 20.1 (11.9–41.2) h for M1, and 17.2 (12.9–30.7) h for M2. In S11 the plasma elimination half life of M1 was prolonged to 76.6 h, and of M2 to 75.4 h. Thus, the elimination defect in S11 was not restricted to the parent drug, but it also involved the two major metabolites M1 and M2. This might be a consequence of a hepatic enzyme deficiency, or be due to impairment of drug excretion.
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  • 35
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    European journal of clinical pharmacology 39 (1990), S. 603-605 
    ISSN: 1432-1041
    Keywords: Galanthamine ; Alzheimer's disease ; stereoselectivity ; cholinesterase inhibition ; side effects ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effect of galanthamine (GAL) and its 2 major metabolites on human cholinesterases has been explored. Epigalanthamine, a diastereomer of GAL, was 130-times less potent in vitro in its effect on acetylcholinesterase (AChE) in erythrocytes than the parent compound, and it did not differ significantly from the ketone galanthaminone. In vivo, the maximal 36–55% inhibition of AChE was approached 30 min after oral administration of 10 mg GAL. The duration of the catalytic inhibition corresponded to an elimination half-life of approximately 5–7 h. GAL was well tolerated in 8/8 healthy volunteers, and 3/4 Alzheimer patients tolerated the drug up to a daily dose of 40 mg.
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  • 36
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    European journal of clinical pharmacology 38 (1990), S. S53 
    ISSN: 1432-1041
    Keywords: nitrates ; pharmacokinetics ; pharmacodynamics ; nitrate tolerance ; isosorbide-5-mononitrate
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Healthy male volunteers received three different dose regimens of a controlled-release form of isosorbide-5-mononitrate (IS-5-MN; 60 mg per tablet). Dose regimen I consisted of a single daily dose of 60 mg given for 5 days. Dose regimen 11 was started with a dose of 60 mg, followed by 30 mg 12 h later and thereafter every 8 h. The last dose, on the 5th day was again 60 mg. In dose regimen III60 mg followed by 30 mg 6 h later were administered every day for 5 days. The peripheral arterial and venous effects of IS-5-MN during the first and last dosing interval were followed by changes in the finger pulse curve, standing systolic blood pressure, heart rate, and venous distensibility. Plasma concentrations of IS-5-MN were measured frequently following the first and the last dose. Following dose regimen I all hemodynamic effects produced by the first dose were maintained during the study. The maximal plasma concentrations were about 400 ng/ml and the trough value, lower than 100 ng/ml. Following dose regimen II the hemodynamic effects of IS-5-MN and sublingual glyceroltrinitrate were completely abolished on the 5th day. Trough plasma concentrations were approximately 300 ng/ml during the entire study period. Following dose regimen III pronounced hemodynamic effects were seen on the 1st day. However, a significant attenuation of the hemodynamic effects was measured on the 5th day, when trough plasma concentrations were between 100 and 230 ng/ml. There was a significant negative correlation between the magnitude of hemodynamic effect remaining on the 5th day (measured by the area under the finger pulse curve) and the trough plasma concentration. Thus, the maintenance of minimum plasma concentrations of IS-5MN of 300 ng/ml or higher produces a rapid development of hemodynamic nitrate tolerance, whereas no tolerance was found when the plasma concentrations were allowed to decline below 100 ng/ml before the next dose was given. A significant attenuation of hemodynamic effects was found when minimum plasma concentrations were between 100 and 230 ng/ml. The degree of attenuation in this concentration range increased with increasing trough plasma concentrations.
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  • 37
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    European journal of clinical pharmacology 39 (1990), S. 199-201 
    ISSN: 1432-1041
    Keywords: netilmicin ; pharmacokinetics ; diurnal variation ; circadian rhythm
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Netilmicin 1.5 mg/kg body weight was administered intravenously every 8 h for 2 days to 8 patients with normal renal function. Significant elevation of mean and trough plasma concentrations was found at 05.00 h and 09.00 h. This was considered to be due to circadian variation, with possible accumulation during the night. The clinical importance of this phenomenon in relation to the development of aminoglycoside toxicity awaits further investigation.
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  • 38
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    Archives of toxicology 64 (1990), S. 61-65 
    ISSN: 1432-0738
    Keywords: Chlorophenoxy acids ; Herbicides ; Pesticides ; Blood-brain barrier ; Protein binding ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The distribution of three common14C-labelled chlorophenoxyacetic acid herbicides (2,4-dichlorophenoxyacetic acid or 2,4-D, 2-methyl-4-chlorophenoxyacetic acid or MCPA, 2,4,5-trichlorophenoxyacetic acid or 2,4,5-T) into the different brain areas was studied in rats pretreated with toxic doses of the herbicides (238–475 mg/ kg). Also, their binding to proteins in rat plasma was determined in vitro by increasing the concentrations of chlorophenoxyacetic acids in the incubate from 0 to 1 mg/ml. Both 2,4-D and MCPA pretreatments increased brain concentrations of14C-labelled herbicides more markedly than 2,4,5-T pretreatments did. No essential differences were found in the distribution between the different brain areas. Protein-unbound fractions of 2,4-D and MCPA in the plasma were clearly higher than those of 2,4,5-T but the highest herbicide concentration increased the protein-unbound fraction of 2,4,5-T more (7-13-fold) than of 2,4-D and MCPA (5-fold). The results suggest that the greater increase in the penetration into the brain of 2,4-D and MCPA than of 2,4,5-T during their intoxication is due to some factors other than the changes in their binding to plasma proteins and mere enhanced diffusion through the blood-brain barrier.
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  • 39
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    Archives of toxicology 64 (1990), S. 365-369 
    ISSN: 1432-0738
    Keywords: Styrene inhalation ; Phenobarbital ; Methylcholanthrene ; Acetone ; Microsomal drug-metabolizing enzymes ; Glutathione ; Thioethers ; Lung ; Liver ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Pulmonary changes in glutathione (GSH) indicated by the concentration of non-protein sulphydryls showed a decrease of 43% in rats exposed for 5 h per day three times to 500 cm3/m3 (2100 mg/m3) styrene vapour. In these rats, only a marginal decrease was observed in the pulmonary cytochrome P450 oxidative metabolism. Following a single 24-h inhalation exposure to 500 cm3/m3 styrene, the decreases in GSH were 66% in lung but only 16% in liver. On the other hand, a multifold increase in the disposition of thioether compounds was found in urine. Pulmonary cytochrome P450-dependent metabolism was decreased, shown by low residual activities of 7-ethoxyresorufin (〈20%), 7-ethoxycoumarin (53%) and 7-pentoxyresorufin O-dealkylases (76%). Epoxide hydrolase and GSH S-transferase enzyme activities which catalyze styrene detoxification were not decreased. Styrene exposure (24 h) of acetone-, phénobarbitalor 3-methylcholanthrene-pretreated rats resulted in pulmonary effects different from each other and from those of styrene alone. Acetone potentiated the lung effect and elevated 1.5-fold urine thioether output. Inducer pretreatment seemed to be a factor aggravating styrene toxicity; in effect this was clearest in acetone-induced rats. In general, GSH depletion accompanied by inhibition of cytochrome P450-dependent oxidative drug metabolism were the earliest biochemical lesions manifested in styrene-exposed lung.
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  • 40
    ISSN: 1432-0738
    Keywords: Di-n-butyl phthalate ; Testes ; Rat ; Toxicity
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Di-n-butyl phthalate (DBP) was administered to young male rats by gavage at the doses of 250, 500 and 1000 mg/kg body weight/day for 15 days. A significant decrease in testes weight was observed at 500 and 1000 mg/kg doses of DBP. Histopathological examination revealed marked degeneration of seminiferous tubules. The activities of testicular enzymes associated with postmeiotic spermatogenic cells, such as sorbitol dehydrogenase and acid phosphatase, were decreased significantly, while that of lactate dehydrogenase was significantly increased, coincident with degeneration of spermatogenic cells. The activities of enzymes associated with premeiotic spermatogenic cells, Sertoli cells or interstitial cells, β-glucuronidase, γ-glutamyl transpeptidase and glucose-6-phosphate dehydrogenase were significantly increased. Thus the alterations in activity of these testicular cell specific enzymes suggest that DBP exposure during early life could affect the testicular functions.
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  • 41
    ISSN: 1432-0738
    Keywords: Chronotoxicology ; Renal toxicity ; Gentamicin ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The effect on kidney damage of the season of year at which gentamicin was administered to rats was studied. Rats received a single intramuscular dose of 200 mg/kg gentamicin at four different times of the day (08.00, 14.00, 20.00 or 02.00 hours. Studies were carried out in January–February, March–April, June–July and October–November. The nephrotoxicity was assessed by the increase of three urinary enzymes: two brush border enzymes, gamma-glutamyl transferase and alanine aminopeptidase, and a lysosomial enzyme: N-acetyl-β-d-glucosaminidase. The results show that when the injection is administered at 20.00 hours in the January–February and the October–November studies and at 08.00 hours in the March–April study and at 14.00 hours in the June–July study there is a significant increase in the excretion of these enzymes. The renal toxicity of gentamicin therefore has circadian variations as well as seasonal variations. The peak enzyme level is displaced from the start to the end of the rest period of rats depending upon the time of year.
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  • 42
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    Experimental brain research 79 (1990), S. 539-546 
    ISSN: 1432-1106
    Keywords: Electroretinogram ; Gratings ; Retina ; Degeneration ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The aim of this study is to investigate in the rat the properties of the pattern electroretinogram (ERG) and to assess whether it depends upon the functional integrity of ganglion cells. Flash and pattern ERG were recorded from urethane anaesthetized hooded rats. The pattern ERG was evoked by phase alternating gratings of various spatial frequencies and contrasts. In the first part of the study we determined how the amplitude of the main harmonic of the pattern ERG (2nd harmonic) varies as a function of stimulus parameters such as spatial and temporal frequency, contrast and mean luminance. In the second part of the study we investigated the effects of the retrograde degeneration of ganglion cells following optic nerve section on the amplitude of pattern ERG. We found that the section of the optic nerve leads to the progressive disapperance of the P-ERG which is almost complete 4 months after surgery. By this time only few axotomized ganglion cells are left. The flash ERG remained unaffected. Thus, the pattern electroretinogram seems to be a simple and sensitive tool to investigate the functional integrity of retinal ganglion cells in rats.
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  • 43
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    Experimental brain research 80 (1990), S. 213-217 
    ISSN: 1432-1106
    Keywords: Visual system ; Auditory system ; Developmental cell death ; Retrograde transport ; Diamidino yellow ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The fluorescent dye diamidino yellow was injected into parts of the developing visual and auditory systems in the rat. The dye was retrogradely transported by projecting neurones and was found to stain pyknotic profiles within the labelled cell populations. It is thus possible to visualize directly the death of neurones which project axons to specific and identified target regions within the nervous system.
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  • 44
    ISSN: 1432-1106
    Keywords: Cyclic AMP ; dl-Propranolol ; Wake-sleep cycle ; Preoptic region ; Hypoxia ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The short-term effects of the intraperitoneal administration of dl-propranolol on the wake-sleep cycle of the rat were studied in relation to the cyclic AMP concentration in the preoptic region and cerebral cortex. The results show that propranolol, but not saline, affected all stages of the wake-sleep cycle, increasing wakefulness, decreasing synchronized sleep and abolishing desynchronized sleep. These effects were associated with a decrement in cyclic AMP concentration both in wakefulness and synchronized sleep. However, this decrement was relatively larger in the preoptic region than in the cerebral cortex. The effects of the drug on cyclic AMP accumulation were also studied in hypoxia, a condition of unspecific brain stimulation. In this condition, the cyclic AMP concentration in both brain regions was found to be higher than that observed during either wakefulness or synchronized sleep. In the hypoxic condition propranolol was found to decrease the nucleotide concentration to the same levels observed in wakefulness and synchronized sleep following its administration. However, no difference in the relative magnitude of the decrement was found between the preoptic region and the cerebral cortex. These findings suggest that in both brain regions the drug acts on a cyclic AMP accumulating system, which may be defined as propranololsensitive. The activity of the propranolol-sensitive system in the preoptic region would appear to be related to wake-sleep processes.
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  • 45
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    Experimental brain research 81 (1990), S. 179-190 
    ISSN: 1432-1106
    Keywords: Acetylcholine ; Fimbria-fornix ; Hippocampus ; Locomotor activity ; Neural grafting ; Radial maze ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Based on three experiments, this study examined whether behavioral and histological effects of fetal septal or hippocampal grafts placed in the denervated hippocampus depend on the duration of post-grafting delays. Each experiment included four groups of rats: sham-operated rats (Sham), rats with aspirative lesions of the fimbria-fornix (Fifo) and rats given both Fifo lesions and intrahippocampal fetal suspension grafts of either septal (Fifo.ST) or hippocampal (Fifo.HT) origin. All rats were tested (i) for home cage activity, (ii) for activity and reactivity in an open field and (iii) for learning ability in a 8-arm radial maze. Except for home cage activity which was also monitored preoperatively, behavioral tests were conducted between 1–2 months postgrafting in Experiment 1 (EXP1), 5–6 months post-grafting in Experiment 2 (EXP2) and 10–11 months postgrafting in Experiment 3 (EXP3). Each test period lasted 3 weeks. Histological controls consisted of acetylcholinesterase (AChE) and cresyl violet staining. Graft size was estimated by computerized image analysis. Normal rats performed well in each experiment. In all experiments, rats with fimbria-fornix lesions showed increased activity in both their familiar (home cage) and unfamiliar (open field) environments, and their performances in the radial maze task were impaired. In no experiment did grafts, whether hippocampal or septal, affect “noncognitive” behavioral variables. However, maze performance was improved by hippocampal grafts in EXP1 (short delay) and by septal grafts in EXP2 (intermediate delay). No graft-induced effect was found in EXP3 (long delay). Concerning AChE-positivity in the dorsal hippocampus, fimbria-fornix lesions reduced staining densities by at least 60%. Both types of grafts were undiscernably AChE-positive, but only septal grafts provided the denervated hippocampus with a significant AChE-positive fiber ingrowth. Differences among groups in density of hippocampal AChE staining were comparable in all three experiments and no correlation between hippocampal AChE-positivity and maze performance was found. Our results suggest that graft-induced recovery from behavioral effects of fimbria-fornix lesions may depend on both the type of tissue implanted (hippocampal vs septal) and the post-grafting delay (1–2, 5–6 and 10–11 months). The recovery observed at a short post-grafting delay with hippocampal grafts and at a longer post-grafting delay with septal grafts was not persistent and concerned only cognitive function as assessed by radial maze performance. Regarding (i) the absence of any correlation between AChE staining and radial maze performance, and (ii) the lack of graft-derived AChE-positive fiber ingrowth in Fifo.HT rats with improved radial maze performance in EXP1, our results also suggest that factors other than graft-derived cholinergic fiber ingrowth might be involved in the graft-induced recovery observed in the radial maze.
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  • 46
    ISSN: 1432-1106
    Keywords: CGRP ; Motoneurons ; Spinal cord ; Immunocytochemistry ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The expression of Calcitonin gene-related peptide (CGRP) has been demonstrated in motoneurons of several species. We have investigated in adult rats the influence of transection of the spinal cord on CGRP immunoreactivity of motoneurons located below the section. Quantative analysis has been performed with computer-assisted image analysis. As early as 48 h after the section, CGRP immunoreactivity is modified, and the reduction is maximal after one month. Then, both the number of immunoreactive cells and the intensity of staining increase until the 5th month. It is concluded that the expression of CGRP is under the influence of supraspinal afferents to the motoneuron.
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  • 47
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    Experimental brain research 80 (1990), S. 489-500 
    ISSN: 1432-1106
    Keywords: Dopamine ; Neuropeptide Y ; Somatostatin ; Tachykinin ; Cholecystokinin ; In situ hybridization ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary In situ hybridization was used to study the expression of prepro-neuropeptide Y (NPY), preprosomatostatin (SOM), preprotachykinin (PPT) and preprocholecystokinin (CCK) mRNA in caudate-putamen and frontoparietal cortex of rat brain with unilateral lesion of midbrain dopamine neurons. Neurons expressing NPY and SOM mRNA showed a similar distribution and the expression of both NPY and SOM appears to be regulated by dopamine in a similar fashion. Following a dopamine deafferentation, the numerical density of both NPY and SOM mRNA producing neurons almost doubled in the lesioned caudate-putamen with no change in the average grain density over positive neurons. Hence, in the intact caudate-putamen dopamine appears to suppress expression of these two neuropeptide genes leading to an activation of both NPY and SOM mRNA expression in many non- or low-expressing neurons when the level of dopamine is decreased. In the fronto-parietal cortex, on the other hand, dopamine appears to stimulate NPY and SOM gene expression. Thus, in the absence of dopamine about half of the NPY positive neurons disappeared. However, for SOM the number of positive neurons did not change, but rather most positive neurons appeared to have down-regulated their SOM mRNA expression. No evidence was found for a change in CCK mRNA expression by the dopamine deafferentation, while PPT mRNA expression decreased in the deafferented caudate-putamen. Consequently, dopamine exerts dissimilar effects on the expression of different neuropeptide genes, that in turn do not respond in the same way in different brain regions.
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  • 48
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    Experimental brain research 81 (1990), S. 18-24 
    ISSN: 1432-1106
    Keywords: Facial motonucleus ; Hemifacial spasm ; Kindling ; Animal model of hemifacial spasm ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary On the basis of results of electrophysiological studies in patients undergoing microvascular decompression (MVD) operations to relieve hemifacial spasm (HFS), we have postulated that the abnormal muscle response characteristically found in patients with HFS is the result of irritation of the facial nerve by the blood vessel that is compressing the facial nerve near its exit from the brainstem in these patients. This abnormal muscle response is seen when one branch of the facial nerve is electrically stimulated and recordings are made from muscles that are innervated by other branches of the facial nerve. We further hypothesized that the facial nucleus is hyperactive in patients with HFS and that the spasm and the abnormal muscle response are results of a phenomenon known as “kindling”. These hypotheses are supported by recent studies showing that chronic electrical stimulation of the facial nerve trunk in rats near the brainstem results in an abnormal muscle response that is similar to that seen in patients with HFS. In this paper, we present the results of recording from the facial motonucleus in rats that had been subjected to repeated electrical stimulation of the facial nerve. The results indicate that the abnormal muscle response in these rats was caused by changes in the function of the facial motonucleus. We interpret these results as showing that the physiological abnormalities that give rise to the signs of HFS in man are located in the facial motonucleus, and that the changes in the function of the nucleus are produced by chronic antidromic neural activity resulting from close contact between a blood vessel and the facial nerve.
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  • 49
    ISSN: 1432-1106
    Keywords: Hippocampus ; CA3 pyramidal cells ; Antiepileptic agent ; Calcium channel blocker ; Verapamil ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary We studied the effects of the organic calcium channel blocker, verapamil, on spontaneous and bicuculline-induced epileptiform burst discharges in CA3 pyramidal cells of hippocampal slices. A transient increase of burst discharge rate was observed in most cells within 30 min after the addition of verapamil (100 μM) to the perfusing medium. Prolonged verapamil perfusions gradually reduced the rate and duration of burst discharges, then abolished them in all tested slices (over periods of 50–150 min) without blocking synaptic transmission. Responses to intracellular injections of current pulses were also gradually affected by verapamil: Action potential amplitude was decreased, action potential duration increased, frequency adaptation increased, amplitude of the fast hyperpolarization following a single action potential decreased, and amplitude and duration of the slow afterhyperpolarization markedly reduced. The amplitude of calcium spikes elicited in slices perfused with tetrodotoxin-containing medium was not affected by verapamil, but the mean velocity of depolarization near the peak of the calcium spike was decreased. Membrane resting potential and input resistance were not affected by verapamil. These results confirm that verapamil is able to suppress epileptiform activity, but suggest that this effect is rather non-specific, due to inhibition of both postsynaptic sodium and calcium conductances.
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  • 50
    ISSN: 1432-1106
    Keywords: Neuropeptide Y ; Dopaminergic mesencephalic pathway ; Nucleus accumbens ; Immunohistochemistry ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The density of neuropeptide Y (NPY) immunostained neurons examined in the rat nucleus accumbens (NAcc) was shown to be constant across the anteroposterior extent of the nucleus and did not present any right-left hemispheric difference. Selective unilateral 6-hydroxydopamine (6-OHDA) lesion of the nigral dopaminergic neurons induced, 15 to 21 days later, a bilateral decrease in the NPY neuron density which was, interestingly, more marked in the contralateral than in the ipsilateral NAcc. Dopamine depletion induced by α-methylparatyrosine treatment elicited a decrease in NPY neuronal density similar in amplitude to that induced by the 6-OHDA lesion in the ipsilateral NAcc suggesting that similar mechanisms underly both NPY responses. In both experimental conditions, changes in NPY immunostaining were quite homogeneous in the two antero-posterior NAcc portions arbitrarily considered. Apomorphine treatment in animals with 6-OHDA injury completely reversed the ipsilateral lesion effect in the anterior part of the NAcc but only partially the contralateral one. In contrast, no significant effect of apomorphine was observed in either side of the NAcc posterior portion. This data suggests the involvement of at least 2 components in the NPY neuron responses to the lesion. The component reversed by apomorphine treatment was presumed to be directly linked to the DA depletion, while the second component not antagonized by apomorphine was considered independant on DA transmission. These data therefore provide morphological evidence for the occurence of complex functional interactions between dopaminergic afferents and NPY-containing neurons within the NAcc.
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  • 51
    ISSN: 1432-1106
    Keywords: Neural grafts ; Basal forebrain ; Neocortex ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Unilateral injections of kainic acid into the basal forebrain in a series of rats resulted in an increase in large amplitude slow waves, a correlated burst-suppression pattern of multi-unit activity, and a decrease in acetylcholinesterase staining in the neocortex ipsilateral to the kainic acid injection. Subsequently, a cell suspension, prepared from rat embryonic basal forebrain tissue, was injected adjacent to the recording electrodes ipsilateral to the kainic acid injection. This produced a gradual recovery of low voltage fast activity (LVFA) and a correlated continuous discharge pattern of multi-unit activity in the neocortex ipsilateral to the kainic acid injection. LVFA recovered more slowly at neocortical recording sites that received an injection of a cell suspension of hippocampal primordial cells or no injection at all. Acetylcholinesterase-positive fibers from the basal forebrain tissue invaded host cortex; no comparable outrgrowths were demonstrable in the hippocampal primordium tissue grafts. Restoration of cholinergic electrocortical activation may play an important role in the improvements in behavioral performance produced by basal forebrain grafts in the cortex in animals with basal forebrain lesions.
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  • 52
    ISSN: 1432-1106
    Keywords: Parvalbumin ; GABA ; Nonpyramidal cell ; Monoclonal antibody ; Lectin ; Proteoglycan ; Cerebral cortex ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Monoclonal antibody HNK-1 is shown to outline selectively a subpopulation of GABAergic neurons containing a specific calcium-binding protein parvalbumin (PV) in the adult rat parietal cortex, using preand postembedding immunocytochemistry at light microscopic level. About 98% of HNK-1 stained cells in the rat parietal cortex were PV immunoreactive. About 95% of HNK-1 immunoreactive cells were also shown to be stained with a lectin, Vicia villosa agglutinin (VVA), with a specific affinity for terminal N-acetylgalactosamine, which has been previously shown to stain selectively a subpopulation of PV-containing GABAergic neurons in this region. Furthermore almost all HNK-1 immunoreactive cells were also stained with a monoclonal antibody, 3B3, which is specific for chondroitin sulfate proteoglycan. 3B3 was shown in the present study to stain selectively a subpopulation of PV-immunoreactive neurons in the adult rat parietal cortex. In addition, a direct comparison of two monoclonal antibodies HNK-1 and VC1.1 revealed that these two were identical in their staining properties and that they defined the same subset of PV-containing GABAergic neurons in the rat parietal cortex.
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  • 53
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    Experimental brain research 79 (1990), S. 217-220 
    ISSN: 1432-1106
    Keywords: Auditory cortex ; Brainstem auditory evoked potential ; Central conduction time ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Central conduction time is the time for an afferent volley to traverse the central pathways of a sensory system. In the present study, central auditory conduction time (CACT) was calculated for the rat, the first such formal measurement in any animal. Brainstem auditory evoked potentials (BAEPs) were recorded simultaneously with the primary response of the auditory cortex (P1). The latency of wave II of the BAEP, which arises in the cochlear nucleus, was subtracted from that of P1. This yielded a mean CACT of 6.6 ms. The results confirm a previous theoretical estimate that CACT in the rat is at least twice as long as central soma-tosensory conduction time.
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  • 54
    ISSN: 1432-1106
    Keywords: Bed nucleus of stria terminalis ; Central nucleus of amygdala ; Phosphoprotein ; Dopamine ; Neuropeptides ; Phosphatase inhibitor ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The distribution and morphology of neurons containing the dopamine- and cyclic AMP-regulated phosphoprotein, DARPP-32, were investigated in the bed nucleus of the stria terminalis (BST) and the central nucleus of the amygdala (CeA). DARPP-32 immunoreactive neurons are numerous in both regions, but are restricted to the lateral dorsal and the lateral juxtacapsular subdivisions of the BST, and the central lateral and lateral capsular subdivisions of the CeA. Immunoreactive neurons in the lateral dorsal BST, and the central lateral and lateral capsular CeA are similar morphologically, while those in the juxtacapsular BST appear to be a subpopulation of striatal mediumsized spiny neurons. The distribution of DARPP-32 immunoreactive neurons in the BST and CeA overlaps considerably with axonal plexuses containing tyrosine hydroxylase (TH), vasoactive intestinal polypeptide (VIP), and calcitonin gene-related peptide (CGRP). These studies provide further evidence of the close relationship between the CeA and BST, and also provide anatomical evidence for possible interactions between neurotransmitters, neuropeptides, and phosphoproteins.
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  • 55
    ISSN: 1432-1106
    Keywords: Histidine decarboxylase ; Histaminergic neurons ; Substance P ; Synaptic interaction ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The synaptic connections between histaminergic neurons and substance P (SP) afferents in the caudal magnocellular nucleus (CM) of the hypothalamus were examined using an immunoelectron microscopic mirror method. SP-immunoreactive (SP-IR) terminals made synaptic contacts with the somata, somatic spines and dendrites of histidine decarboxylase immunoreactive (HDC-IR) neurons. This suggests that SP afferents exert monosynaptic influence on the central histaminergic neuronal system.
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  • 56
    ISSN: 1432-1106
    Keywords: Motor cortex ; Somatotopic representations ; Peripheral nerve injury ; Neural plasticity ; Motor control ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary In the accompanying paper (Sanes et al. 1989), we demonstrated that the map of motor cortex (MI) output was reorganized when examined 1 week to 4 months after a motor nerve lesion in adult rats. The present experiments measured the extent of functional reorganization that occurs within the first hours after this lesion. Shifts in MI output were examined by testing the effect of stimulation at a site in MI vibrissa area before and up to 10 h after nerve section of the branches of the facial nerve that innervate the vibrissa. Immediately following nerve transection, no movement or forelimb EMG activity was evoked by intracortical electrical stimulation within the vibrissa area. Within hours of the nerve transection, however, stimulation elicited forelimb EMG responses that were comparable to those obtained by stimulating within the pre-transection forelimb area. Remapping of MI after nerve transection indicated that the forelimb boundary had shifted about 1 mm medially from its original location into the former vibrissa territory. Forelimb EMG could be evoked for up to 10 h within this reorganized cortex. These results indicated that the output circuits of MI can be quickly reorganized by nerve lesions in adult mammals.
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  • 57
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    Experimental brain research 81 (1990), S. 53-58 
    ISSN: 1432-1106
    Keywords: Vasopressin ; Oxytocin ; Adrenocorticotrophic hormone ; Emotional stress ; Opioid ; Prolactin ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The effects of an opioid receptor antagonist, naloxone (NAL), were studied on the changes in pituitary hormone secretion induced by emotional stress. Male Wistar rats were trained with tone stimuli paired with electric footshocks and tested with the tone and environmental cue signals for emotional stress of fear acquired by learning as described previously (Onaka et al. 1988). Rats received s.c. injected NAL 30 min before testing at doses of 0, 0.2, 1.0, 5.0 and 25.0 mg/kg b.w. Half the rats were injected with 0.5 M NaCl (20 ml/kg b.w.) together with NAL. In these hypertonic rats plasma vasopressin level was slightly increased after NAL. The increment was statistically significant in control groups but not in experimental groups. However the suppression of vasopressin secretion by emotional stimuli was not changed by NAL. Plasma oxytocin levels were extremely high and not significantly different among experimental, unshocked control and untested control groups. NAL further increased the oxytocin level dose-dependently. NAL did not significantly change plasma adrenocorticotrophic hormone (ACTH) levels and hence did not modify the augmentative response in ACTH secretion to emotional stimuli. Plasma prolactin level was significantly elevated after emotional stimuli and NAL depressed the prolactin level in each of experimental and control groups. After NAL, the magnitude of the facilitatory response in prolactin secretion to emotional stimuli was decreased. Motor activity and its suppressive response to emotional stimuli were not influenced by NAL. In another half of rats under a normal osmotic condition the vasopressin response to emotional stimuli was not affected by NAL. NAL further augmented potentiation of oxytocin secretion after emotional stimuli dose-dependently. Effects of NAL on ACTH level, prolactin level and motor activity were similar to those in rats under hypertonic conditions. These results demonstrate that endogenous opioids are selectively and differentially involved in hypothalamo-hypophysial responses to fear-related emotional stress.
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  • 58
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    Experimental brain research 81 (1990), S. 85-94 
    ISSN: 1432-1106
    Keywords: Spinocerebellar neurons ; Dorsal root projections ; Double labeling ; Choleragenoid ; Fluorogold ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The aim of this study has been to investigate projections to spinocerebellar cell groups from lumbar dorsal root ganglia (DRGs) in the rat. The binding subunit of cholera toxin conjugated to horseradish peroxidase (B-HRP) was used to label primary afferent fibers. Spinocerebellar neurons were labeled retrogradely by Fluoro-Gold (FG). To determine the orientation of dendrites, retrogradely labeled spinocerebellar neurons were studied, following injections of wheat germ agglutinin conjugated horseradish peroxidase (WGA-HRP) into cerebellum. FG or WGA-HRP labeled neurons were found mainly in laminae V and VII, in the lateral group of lamina IX, in Clarke's column (CC) and in the dorsal funiculus. B-HRP labeled primary afferent fibers overlapping with FG labeled cells were observed at all these locations after injections of B-HRP into different DRGs. The overlap in lamina V was found mainly medially and dorsolaterally. CC was found to receive dense projections from DRGs L1–6. In the lumbar part of CC, labeling from DRGs L4–5 overlapped and was distributed over the entire mediolateral extent of the CC, whereas labeling from DRGs L1–3 was somatotopically organized and projected to successively more dorsomedial areas. The central area of lamina VII showed moderate labeling from DRGs L3–5. The lateral group of lamina IX received only smaller amounts of labeled fibers from DRGs L3–5.
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  • 59
    ISSN: 1432-1106
    Keywords: Hypoglossal nucleus ; Catecholamines ; Norepinephrine ; Immunocytochemistry ; Electron microscopy ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary A correlative light and electron microscopic investigation was undertaken to determine the morphology and distribution of catecholamine (CA)-containing axon terminals in the hypoglossal nucleus (XII) of the rat. This was accomplished immunocytochemically with antibody to tyrosine hydroxylase (TH). The major findings in this study were the following: 1) Immunoreactive profiles were found throughout XII and included unmyelinated axons, varicosities, axon terminals and dendrites; 2) Nonsynaptic immunoreactive profiles (preterminal axons, varicosities) were more frequently observed (55.2%) than synaptic profiles (43.5%); 3) CA-containing axon terminals ending on dendrites were more numerous (71.8%) than those synapsing on somata (25.4%) or nonlabeled axon terminals (2.7%); 4) The morphology of labeled axon terminals was variable. Axodendritic terminals typically contained numerous small, round agranular vesicles, a few large dense-core vesicles and were associated with either a symmetric or no synaptic specialization, axosomatic terminals were often associated with a presynaptic membrane thickening or a symmetric synaptic specialization and contained small, round and a few elliptical-shaped vesicles, while axoaxonic synapses formed asymmetric postsynaptic specializations; and 5) CA-positive dendritic processes were identified in XII. These findings confirm the CA innervation of XII, and suggest a complex, multifunctional role for CA in controlling oro-lingual motor behavior.
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  • 60
    ISSN: 1432-1106
    Keywords: Epileptic brain damage ; Excitatory amino acids ; Status epilepticus ; Substantia nigra ; SN ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary We have developed a model system in which the mechanisms of neuronal damage due to hyperexcitation can be studied in isolation and where extended observation periods can be used. Substantia nigra pars reticulata (SNPR) develops a hypermetabolic necrosis following status epilepticus (Nevander et al. 1985; Auer et al. 1986). We transplanted rat fetal nigral area alone or together with fetal frontal neocortex to the anterior chamber of the eye in adult rats. Following 3 months of transplant maturation the hosts were subjected to status epilepticus for 60 min. In single nigral transplants no sign of structural damage was found. In the double transplants of frontal cortex and the substantia nigra a tissue necrosis had developed in the nigral part. This was demonstrated by a total loss of glial fibrillary acidic protein (GFA) immunoreactivity within a circumscribed necrotic region in the nigral part of the double transplant. Such a loss of GFA immunofluorescence had also developed in the host SNPR, as we have earlier shown (Eriksdotter Nilsson et al. 1987). Thus, intraocular brain tissue transplants provide a unique model for studies on the development of neuronal damage and functional dependence between different neuronal structures for the development of such damage.
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  • 61
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    Experimental brain research 81 (1990), S. 313-317 
    ISSN: 1432-1106
    Keywords: Valproic acid ; Ionic currents ; Cerebral cortex ; Patch clamp ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Rat neocortical neurons in culture were subjected to the whole cell mode of voltage clamping under experimental conditions designed to study Na+, Ca{2su+} and K+ currents in isolation. Following pharmacological blockade of most of the Ca2+ and K+ channels, depolarizing commands which brought the membrane potential from — 80 to +10 mV elicited an inward current. This current was sensitive to tetrodotoxin (TTX) and was therefore caused by the opening of voltage-dependent channels permeable to Na+. Extracellular application of the antiepileptic drug valproic acid (VPA, 0.2–2mM) reduced in a dose-related, reversible way this Na+ current. VPA also evoked an increase of the voltage-dependent inward current recorded in the presence of TTX and thus presumably carried by Ca2+; this effect was seen in the presence of doses of VPA larger than 0.5 mM and was not reversible. Two types of outward K+ currents evoked by depolarizing steps in the presence of Na+ and Ca2+ channels blockers were not affected by VPA (up to 5 mM). Our data indicate that doses of VPA that are within the range present when it is used as an anticonvulsant, can influence inward currents generated by rat neocortical cells in culture. The reduction of the Na+, inward current is in line with findings obtained in mouse neurons by using standard intracellular recording techniques. This effect might represent an important mechanism of action for VPA in neocortex.
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  • 62
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    Experimental brain research 82 (1990), S. 575-584 
    ISSN: 1432-1106
    Keywords: Ca2+- and phospholipid-dependent protein kinase ; Visual cortex ; EM-immunocytochemistry ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary In the primary visual cortex of adult rats the cellular and subcellular distribution of protein kinase C isozymes II and III (PkCII/III) was examined by immunohistochemical methods with a monoclonal antibody against PkCII/III. Strong PkC(II/III)-immunoreactivity was found in neurons and astrocytes. Immunopositive neurons exhibited morphological features characteristic for both pyramidal and non-pyramidal cells. They were distributed in layers II through VI but were concentrated in layers II/III. At the electron microscopic level immunoprecipitate was found predominantly in distinct regions of the somata, except the nuclei, and only a few labeled dendrites and axons were seen. Two different patterns of cytoplasmic immunoreactivity could be distinguished. In most neurons, PkC(II/III)-staining was confined to cytoplasmic spots associated with the Golgi complex, while a few neurons exhibited additional labeling in the vicinity of the cell membrane. Moreover, PkC(II/III)-immunoreactivity was present in numerous astroglial processes and in the perikaryal cytoplasm of a subpopulation of astrocytes. Present data provide morphological indications for specifie functions of PkC isozymes II and III in neurons as well as in astrocytes.
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  • 63
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    Experimental brain research 82 (1990), S. 641-650 
    ISSN: 1432-1106
    Keywords: Neural transplantation ; Acetylcholine ; Hippocampus ; Aging ; Spatial memory ; Housing condition ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Age-related cognitive impairments were studied in rats kept in semi-enriched conditions during their whole life, and tested during ontogeny and adult life in various classical spatial tasks. In addition, the effect of intrahippocampal grafts of fetal septal-diagonal band tissue, rich in cholinergic neurons, was studied in some of these subjects. The rats received bilateral cell suspensions when aged 23–24 months. Starting 4 weeks after grafting, they were trained during 5 weeks in an 8-arm maze made of connected plexiglass tunnels. No age-related impairment was detected during the first eight trials, when the maze shape was that of a classical radial maze in which the rats had already been trained when young. The older rats were impaired when the task was made more difficult by rendering two arms parallel to each other. They developed an important neglect of one of the parallel tunnels resulting in a high amount of errors before completion of the task. In addition, the old rats developed a systematic response pattern of visits to adjacent arms in a sequence, which was not observed in the younger subjects. None of these behaviours were observed in the old rats with a septal transplant. Sixteen weeks after grafting, another experiment was conducted in a homing hole board task. Rats were allowed to escape from a large circular arena through one hole out of many, and to reach home via a flexible tube under the table. The escape hole was at a fixed position according to distant room cues, and olfactory cues were made irrelevant by rotating the table between the trials. An additional cue was placed on the escape position. No age-related difference in escape was observed during training. During a probe trial with no hole connected and no proximal cue present, the old untreated rats were less clearly focussed on the training sector than were either the younger or the grafted old subjects. Taken together, these experiments indicate that enriched housing conditions and spatial training during adult life do not protect against all age-related deterioration in spatial ability. However, it might be that the considerable improvement observed in the grafted subjects results from an interaction between the graft treatment and the housing conditions.
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  • 64
    ISSN: 1432-1106
    Keywords: Immunohistochemistry ; Monoclonal antibody ; GABAA-receptors ; Tissue cultures ; Spinal cord ; Brain stem ; Cerebellum ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Explant cultures of rat spinal cord, brain stem and cerebellum were used to visualize GABAA-receptors by means of immunohistochemistry. For these studies we have incubated the cultures with the monoclonal antibody bd 17 against the β-subunit of the GABAA/benzodiazepine/chloride channel complex. In spinal cord cultures, many interneurones were immunoreactive whereas only a small number of large neurones, probably motoneurones was specifically stained. In brain stem cultures, groups of large and medium-sized neurones showed immunoreactivity. In cultures of cerebellum, a great number of neurones was specifically stained. Granule cells showed the strongest immunoreactivity whereas other neurones, presumably Purkinje cells and interneurones, were only moderately stained. The immunoreactivity was mainly confined to the cell bodies of the neurones while their processes were only weakly or not stained. In contrast to neurones, no immunoreactivity could be detected on astrocytes.
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  • 65
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    Experimental brain research 83 (1990), S. 67-78 
    ISSN: 1432-1106
    Keywords: Nociception ; Withdrawal reflexes ; Flexion reflex ; Spinal cord ; Pain ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary 1. The organization of the nociceptive hind-limb withdrawal reflexes was investigated in 93 halothane/nitrous oxide anesthetized rats. Electromyographical techniques were used to record reflex activity in single motor units. 2. Most of the hindlimb muscles were activated by noxious mechanical stimulation of the skin of the ipsilateral hindlimb. These were the plantar flexors of the digits, the pronators of the paw, the dorsiflexors and the plantar flexors of the ankle, the flexors of the knee, the flexors of the hip and the adductors. By grading the stimulus intensity it was shown that all these muscles received input from cutaneous nociceptors. 3. Noxious stimulation of the skin failed to activate the obturator, knee extensors and m. tibialis posterior and, in most rats tested, m. semimembranosus and m. adductor magnus. The plantar flexors of the ankle, while exhibiting a clear nocireceptive field in all rats tested, had a high threshold and responded much more weakly than the dorsiflexors of the ankle. Thus, responses in muscles which oppose gravity in the standing position were either very weak or absent. 4. The present study shows that each of the activated hindlimb muscles has a highly organized noci-receptive field on the skin, which is related to the withdrawal movement caused by the muscle itself. Each of the muscles normally causes the withdrawal of its receptive field when the foot is on the ground. The skin area most effectively withdrawn, in this situation, corresponds to the most sensitive area of the nocireceptive field. However, with the exception of the plantar flexors of the digits and/or the ankle, each of the hindlimb muscles also withdraws the major parts of their receptive fields when the foot is off the ground. The locations of the noci-receptive fields were independent of the position of the hindlimb. These characteristics of the nociceptive withdrawal reflexes are the basis for their “local sign” (Sherrington 1906). 5. The threshold and the time course of reflex activation were different in different muscles. However, muscles with a similar action; the plantar flexors of the digits, the pronators of the paw, the dorsiflexors of the digits, the flexors of the knee and the adductors, respectively, had similar thresholds and time courses. Furthermore, the threshold and latency of activation of each muscle increased towards the border of its nocireceptive field, reflecting a decreasing sensitivity. These findings explain the progressive recruitment of muscles during increasing strength of noxious stimulation, termed “irradiation” (Sherrington 1906). 6. It is suggested that the nociceptive withdrawal reflexes are organized as separate reflex paths to individual muscles, each of which has a well organized cutaneous nocireceptive field.
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  • 66
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    Experimental brain research 83 (1990), S. 131-136 
    ISSN: 1432-1106
    Keywords: Vasopressin release ; Brain renin-angiotensin system ; Brain prostanoids ; Prostaglandin D2 ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Experiments were carried out in conscious, unrestrained, male rats to evaluate possible interactions between brain prostanoids and the brain renin-angiotensin system in the control of vasopressin release and in cardiovascular regulation. The intracerebroventricular (icv) administration of prostaglandin D2 (PGD2) resulted in transient increases in the plasma vasopressin concentration (PAVP) and heart rate and a gradual increase in mean arterial blood pressure (MABP). Pretreatment icv with saralasin, an angiotensin II-receptor antagonist, moderately attenuated the vasopressin response to PGD2, but had no effect on the heart rate and blood pressure responses. Angiotensin II icv increased both PAVP and MABP. This vasopressin response was almost completely prevented by prior icv meclofenamate, a cyclooxygenase inhibitor, and the blood pressure response was attenuated. These observations, combined with previous studies of the role of central angiotensin II and central prostanoids in the physiological control of vasopressin release, suggest that there may be important interactions between brain prostanoids and the brain renin-angiotensin system in this control.
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  • 67
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    Experimental brain research 80 (1990), S. 409-414 
    ISSN: 1432-1106
    Keywords: Olfactory bulb ; Paired pulse inhibition ; MK801 ; Ketamine ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary We have investigated the effects of the phencyclidine like-compounds ketamine and MK801 on the evoked field potentials of rat olfactory bulb. Low doses of ketamine (3–6 mg/kg) blocked the inhibition of mitral cells by granule cells evoked by stimulation of lateral olfactory tract fibres or by stimulation of olfactory nerve. This blockade was not accompanied by a decrease in granule cell excitation as revealed by field potential recording. MK801 had a similar effect on the inhibition of mitral cells evoked by stimulation of the lateral olfactory tract. As ketamine does not influence the inhibitory action of GABA (Anis et al. 1983) these results suggest that both ketamine and MK801 block inhibition by an action on intrinsic excitatory feed-back circuits in the olfactory bulb.
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  • 68
    ISSN: 1432-1106
    Keywords: Ventroposterolateral thalamus ; Primary somatosensory cortex ; Afferent suppression ; Locomotion ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Single neurons were simultaneously recorded in the forepaw areas of the primary somatosensory (SI) cortex and ventroposterolateral (VPL) thalamus of awake rats during rest and running behaviors. Movement dependent changes in somatic sensory transmission were tested by generating post-stimulus histograms of these neurons' responses to stimulation through electrodes chronically implanted under the skin of the forepaw, while the aminal ran on a timed treadmill. As viewed in post-paw-stimulus histograms, the evoked unit responses (EURs) could be differentiated into short (4.5 ± 0.1−10.9 ± 0.2 ms) and longer (12.9 ± 0.4 31.3 ± ± 0.9 ms) latency components (“SEURs” and “LEURs”, respectively). The magnitudes of firing during these responses were measured and normalized as percent increases over background firing. By comparison with resting behavior, treadmill movement suppressed both SEURs and LEURs in the thalamus, as well as the cortex. The SEURs, however, were much more strongly suppressed in the SI cortex (−48.3 ± 2.7%) than in the VPL thalamus (−28.1 ± 6.7%). By contrast, similar magnitudes of suppression of LEURs were found in the SI (−25.8 ± 8.6%) and VPL (−26.5 ± 11.1%). These results suggest that the suppression of LEURs observed in the SI cortex may result from modulatory actions on subcortical circuits. Major suppression of SEURs, on the other hand, may occur intracortically, with a minor component ocurring subcortically. Thus, VPL thalamus and SI cortex in the rat appear to be differentially subject to movement related modulation of sensory transmission.
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  • 69
    ISSN: 1432-1106
    Keywords: 6-hydroxydopamine ; Neonatal ; Dopamine ; D1 receptors ; Dopamine D2 receptors ; Cyclic adenosine 3′∶5′-monophosphate ; Adenylate cyclase ; DARPP-32 ; Nonlinear curve fitting ; Random-effects ; model ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Newborn male Sprague-Dawley rats were treated neonatally with an intracisternal injection of 75 μg 6-hydroxydopamine (6-OHDA) following desipramine pretreatment in order to induce a permanent selective dopamine (DA) lesion. At 60–70 days of age a massive loss of tyrosine hydroxylase (TH) immunoreactive (IR) cells was seen in substantia nigra. The TH-IR terminal density was reduced by 92% in striatum, 77% in nucleus accumbens and by 72% in tuberculum olfactorium. Quantitative autoradiography using 3H-SCH-23390 and 3H-spiperone did not reveal any alteration of DA D1 and D2 receptor binding in the denervated regions studied. Furthermore, no change in the Bmax or Kd of 3H-SCH-23390 or 3H-spiperone in vitro binding was observed in membrane preparations of striatum following the neonatal DA lesion. Basal and DA-stimulated accumulation of cAMP was increased in striatal membrane preparations of the neonatally DA-lesioned rats. No alteration of the immunoreactivity of the D1 receptor associated phosphoprotein dopamine- and adenosine 3′∶5′-monophosphate-regulated phospho-protein (DARPP-32), was observed as visualized using quantitative immunohistochemistry. Thus, neonatal DA lesions seem to induce a selective functional supersensitivity reflected by an enhanced activity of D1 receptor-coupled adenylate cyclase, without any alteration in the number or affinity of D1 and D2 receptor sites. Further-more, the appearance of DARPP-32 seems to be independent of intact DA input during development.
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  • 70
    ISSN: 1432-1106
    Keywords: Sleep ; Voltammetry ; High performance liquid chromatography (HPLC) ; Serotonin (5-HT) ; 5-hydroxyindoleacetic acid (5-HIAA) ; Corticotropin-like intermediate lobe peptide (CLIP) ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary In the present work, differential pulse voltammetry (DPV) measurements of the extracellular fraction of 5-hydroxyindole compounds were performed in rats under long-term chronic conditions. In the nucleus Raphe Dorsalis (n.RD), the voltammetric signal measured at +300 mv (peak 3) disappeared completely 70 to 90 min after injection of Clorgyline (10 mg/kg), a monoamine oxidase inhibitor type A (MAOI-A); the signal measured in such conditions is thus dependent upon extracellular 5-hydroxyindoleacetic acid (5-HIAA peak 3). Deprenyl, an MAOI type B, at the same dose, induced only a slight increase in peak 3 height; according to the fact that MAO-B is selectively located in the 5-HT neurons and since their inhibition does not decrease 5-HIAA peak 3 nor the endogenous 5-HIAA content as measured with High Performance Liquid Chromatography (HPLC), 5-HIAA measured with DPV in the extracellular fluid of untreated animals might come from 5HT released and metabolized by MAO-A outside the 5-HT neurons. In animals implanted for measurements of both voltammetric and polygraphic parameters, the 5-HIAA peak 3 measured mainly in the anterior and ventral part of the n.RD exhibited large increases in its height during slow-wave sleep (SWS: +39%) and paradoxical sleep (PS=+71%) as compared to the waking state (W=100%); these variations could reflect the dendritic release of 5-HT. In the Caudate nucleus (n.Cd) the same voltammetric signal presented reverse fluctuations, i.e. an increase during W and a decrease during SWS and PS. Intracerebroventricular administration of Corticotropin-Like Intermediate lobe Peptide (CLIP, 10 ng/2 μl) induced an increase in PS duration (+51%) preceded and accompanied by an increase in the n.RD 5-HIAA peak 3 height (+50%).
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  • 71
    ISSN: 1432-1106
    Keywords: Neonatal grafts ; Nigral transplant ; Dopamine ; Aphagia ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Previous studies have shown that dopamine-rich nigral grafts, implanted bilaterally into the intact neonatal brain, will provide some protection from the eating disorders induced by subsequent nigrostriatal 6-OHDA lesions. This has been repeated in the present study using unilaterally transplanted nigral grafts. Following adult lesions, the control animals displayed the full syndrome of aphagia, adipsia and akinesia. By contrast, 37% of the rats in the transplanted group recommenced eating following the adult lesion. Recovery was related to the size and position of the graft: protection was associated in particular with transplants located in the posterior-ventral neostriatum. The results are discussed in terms of specific patterns of graft-host interaction that may underlie protection of the regulation of eating from the loss of forebrain dopamine systems.
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  • 72
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    Experimental brain research 80 (1990), S. 196-200 
    ISSN: 1432-1106
    Keywords: Long-term depression ; Longterm potentiation ; Hippocampus ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary In slices of rat hippocampus, a train of conditioning pulses that would produce long-term potentiation (LTP) if applied to afferent inputs was found to produce a long-lasting depression of Schaffer collateral/ commissural synapses on CA1 cells when instead it was applied to the CA1 axons. The depression lasted undiminished for up to 2 h (the maximum duration of recording). Intracellular recording showed that long-term depression (LTD) of e.p.s.p. amplitude occurred in 66% of cells when this antidromic conditioning stimulation was delivered in normal medium, and in 100% of cells when the antidromic stimulation was delivered in medium containing sufficient Mg++ to block all synaptic transmission. We infer that the difference is because conditioning stimuli sometimes activated test synapses in normal Mg++ but could not in high Mg++. The fact that LTD could be induced in high Mg++ eliminates enhanced inhibitory feedback as a possible mechanism of the long lasting synaptic depression and demonstrates that the mechanism is probably postsynaptic. Resting membrane potential and cell input resistance were the same before and after conditioning, so persisting changes in these postsynaptic parameters can not be the explanation for LTD. LTD of the sort described in this paper could have significant implications for models of learning and memory.
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  • 73
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    Experimental brain research 81 (1990), S. 372-376 
    ISSN: 1432-1106
    Keywords: Spinocerebellar neurons ; Dorsal funiculus ; Spinal cord ; Neurogenesis ; Fluoro-gold ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Nerve cell bodies located within the white matter of the dorsal funiculus (DF neurons) have been previously observed but not described in detail. The present study examines the morphology, ontogeny, and projection of DF neurons utilizing Fluoro-Gold as a retrograde tracer, alone, and in combination with tritiated thymidine autoradiography in the spinal cord of the rat. DF neurons were consistently labelled in spinal segments T13 through L2 following injections of Fluoro-Gold into the cerebellum. The cell bodies of DF neurons were small to medium in size, fusiform to multipolar in shape, and were located on the side ipsilateral to the injection site. Cell counts revealed approximately five labelled cells per millimeter along the longitudinal axis. An examination of neurogenesis using tritiated thymidine combined with Fluoro-Gold showed that DF neurons have relatively late birthdates as do other spinocerebellar neurons of the dorsal horn. Retrograde axon tracing studies in the spinal cord using Fluoro-Gold showed that DF neurons project rostrally via the ipsilateral lateral funiculus. The significance of the presence of nerve cells in the dorsal funiculus is unclear, but judging from their location, ontogeny, and projection, DF neurons are probably derived from the same pool of neurons as those in the Nucleus dorsalis.
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  • 74
    ISSN: 1432-1106
    Keywords: Kindling ; Hippocampus ; Neural transplantation ; Locus coeruleus ; Idazoxan ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Intrahippocampal cell suspension grafts, prepared from the locus coeruleus region of rat fetuses, have previously been shown to retard seizure development in rats made hypersensitive to hippocampal kindling by a lesion of the forebrain noradrenergic system. The objective of the present study was to provide evidence that the seizure-suppressant effect elicited by the grafts is mediated via noradrenergic mechanisms. Two groups of rats received 6-hydroxydopamine in the lateral ventricle and then bilateral intrahippocampal locus coeruleus grafts. After 3 months, the grafted animals and a group of normal rats were subjected to hippocampal kindling. One group of grafted animals and the normal rats were injected intraperitoneally with the alpha-2 adrenergic receptor blocker idazoxan before each kindling stimulation. The other grafted rats received vehicle injections. The development of seizures was significantly faster in the grafted and normal rats that had been given idazoxan than in the grafted rats that had not been subjected to alpha-2 receptor blockade. Our data suggest that the seizure-suppressant action exerted by grafts of fetal locus coeruleus in hippocampal kindling is mediated via noradrenergic mechanisms, most likely via activation of postsynaptic alpha-2 adrenoreceptors.
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  • 75
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    Experimental brain research 81 (1990), S. 500-508 
    ISSN: 1432-1106
    Keywords: Dentate gyrus ; Ammon's horn ; Synapses ; Golgi-gold labeled terminals ; Light and electron microscopy ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Recent studies have indicated that hippocampal basket cells in both the dentate gyrus and Ammon's horn develop their somal and dendritic features during the first two postnatal weeks in rats. Their axon terminals form exclusively symmetric synapses that are found as early as 5 postnatal days in both regions. The present study used Golgi-electron microscopic material from 10 and 16 day old rats to demonstrate that the axon terminals of basket cells form synapses not only with somata, dendrites, and dendritic spines as reported for adult material but also with axon initial segments. However, the terminals forming synapses with axon initial segments and dendritic spines represent only a minor portion of the total number of basket cell terminals. Quantitative results indicate that 36–62% of the total number of these terminals form axosomatic synapses and 32–50% form axodendritic synapses depending on the analyzed cell. These data indicate that hippocampal basket cells have an axonal distribution similar to that found for cortical basket cells.
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  • 76
    ISSN: 1432-1106
    Keywords: Axonal tracing ; Neural transplants ; Fluoro-Gold ; Nuclear Yellow ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The ability of axonal regeneration of identified adult basal forebrain (BFB) neurons was examined after homotopic grafting of fetal neocortical tissue to a lesion cavity in the frontal neocortex. Using a four step experimental procedure, adult rats first received an injection of the fluorescent dye Fluoro-Gold (FG) into the sensorimotor cortex in order to label those neurons with projections to the area by retrograde axonal transport. After one week the injection area was removed by aspiration, leaving a cavity in the neocortex. One week later a block of fetal (E14) frontal cortical tissue was placed in the cavity. The animals were then allowed to survive for 6 weeks before a second fluorescent tracer, Nuclear Yellow (NY), was injected into the transplant. The animals were sacrificed 24 h later and analyzed by fluorescence microscopy. Both single labeled, FG and NY containing neurons and double labeled neurons containing both tracers were found in the BFB. The results demonstrate that adult BFB neurons can reestablish cortical projections into fetal cortical grafts (double labeled neurons), and they suggest that other BFB neurons, not initially innervating the lesioned cortical area, have sprouted into the transplant (NY labeled neurons).
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  • 77
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    Experimental brain research 81 (1990), S. 649-653 
    ISSN: 1432-1106
    Keywords: Motoneurons ; Musculotopic organization ; Whisker follicle ; Brainstem ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary WGA-HRP, HRP and fluorescent tracers were used to determine the representation of the facial muscles in the facial motor nuclear complex (FMNC) of the newborn rat. Tracer injections of the superficial cervical and anterior mandibular portions of platysma, the orbicularis oculi muscle, the nasolabial musculature and the posterior auricular musculature revealed an adultlike topographic organization across FMNC subnuclei. Tracer delivery to individual vibrissa follicle loci of the whiskerpad also demonstrated an adult-like musculotopic organization within the lateral subnucleus.
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  • 78
    ISSN: 1432-1106
    Keywords: NMDA receptor ; Quisqualate/kainate receptor ; Excitatory amino acid ; Medial vestibular nucleus ; Slice ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The actions of excitatory amino acid (EAA) antagonists on synaptic inputs to neurons in the rat medial vestibular nucleus (MVN) from ipsilateral vestibular afferents and vestibular commissures were studied in brain stem slice preparations. Antagonists used were 2-amino-5-phosphonovalerate (APV), a selective antagonist for the N-methyl-D-aspartate (NMDA) type of EAA receptors, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), a selective antagonist for the quisqualate/kainate (non-NMDA) type of EAA receptors and kynurenate (KYNA), a broad spectrum antagonist for the three types of EAA receptors. MVN neurons were classified as having mono- or polysynaptic inputs from vestibular afferents and commissural fibers by calculating synaptic delay. An application of APV through the perfusion medium suppressed 82% of cells activated monosynaptically from commissures, while it suppressed only 9% of cells activated monosynaptically from vestibular afferents. The application of KYNA proved much less selective, suppressing 83% of the former group of cells and 93% of the latter. CNQX suppressed almost all the cells of both groups. The sensitivity of monosynaptic inputs to KYNA, CNQX or APV was not significantly different from that of polysynaptic inputs irrespective of sources of inputs. These results suggest that excitatory synaptic inputs to MVN neurons are mediated mainly through non-NMDA type of EAA receptors from vestibular afferents and through NMDA as well as non-NMDA types of EAA receptors from commissures.
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  • 79
    ISSN: 1432-1106
    Keywords: Dynorphin ; Substance P ; Neurokinin A ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The striatonigral pathway contains several neurotransmitters which may regulate the activity of the nigrostriatal dopamine projection in the rat. This was investigated by measuring extracellular dopamine levels in the striatum, using microdialysis, after injections of GABA (300 nmol/0.2 μl), dynorphin A (0.5 nmol/0.2 μl), substance P (0.07 mnol/0.2 μl) or neurokinin A (0.09 nmol/0.2 μl) into the ipsilateral substantia nigra, pars reticulata (SNR). Intranigral injections of GABA or dynorphin A inhibited, while intranigral injections of substance P or neurokinin A stimulated dopamine levels in the ipsilateral striatum. In rats with ibotenic acid lesions (2.5 μg/0.5 μl) in the SNR, intranigral injections of GABA or dynorphin A inhibited, while intranigral injections of substance P or neurokinin A stimulated dopamine levels in the ipsilateral striatum. These responses were not significantly different than those in unlesioned rats. Analysis of the intranigral lesion with in situ hybridization revealed a heavy loss of glutamic acid decarboxylase mRNA expression in the SNR and a significant loss of tyrosine hydroxylase (TH) mRNA expression in the SNC. Immunohistochemical analysis revealed a disappearance of TH-Like immunoreactivity (LI) im dendrites in the SNR, a considerable loss of TH-LI cell bodies in the SNC and a restricted loss of neuropeptide K-LI in the SNR around the tip of the injection cannula. Furthermore, lesioned rats rotated ipsilateral to the lesion after apomorphine (1 mg/kg, s.c.), indicating that the basal ganglia output mediated via the SNR GABA neurons was impaired on the lesioned side. Analysis of the striatum revealed that a dense TH-LI fiber network could still be seen on the lesioned side. Furthermore, basal and amphetamine stimulated extracellular dopamine levels in the striatum on the lesioned side were not significantly depleted. This indicates that the ascending nigrostriatal dopamine projection was functionally intact on the lesioned side. These findings indicate that intranigral GABA, dynorphin A, substance P and neurokinin A modulation of ipsilateral striatal dopamine release is mediated via direct action on the nigrostriatal projection. Thus, it is suggested that the striatonigral pathway, which contains GABA, dynorphin, substance P and neurokinin A, exerts a direct regulatory effect on the activity of the nigrostriatal dopamine projection.
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  • 80
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    Experimental brain research 82 (1990), S. 401-407 
    ISSN: 1432-1106
    Keywords: Cerebellum ; Development ; Graft ; Structure ; Purkinje cell ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary A prominent feature of the mammalian cerebellum is its organization into parasagittal compartments. One marker of such compartments is the zebrin I molecule that is expressed by bands of Purkinje cells (PC). In order to understand better the basis for the development of this organization, we have transplanted dissociated rat cerebellar anlage, taken during the period of proliferation of PC precursors, into kainic acid lesioned adult rat cerebellum. As previously observed, the resultant grafts exhibited trilaminar structures reminiscent of the normal cerebellum. In every case, the PC in the resultant grafts were organized into zebrin I + and — compartments. In one case, most of the grafted PC were integrated into a region of PC deficient host molecular layer that was induced by pretreatment with kainic acid. Clear bands defined by zebrin I reactivity were seen where groups of the grafted PC had entered the host molecular layer. These bands did not correlate in distribution or size with host bands. Hypotheses compatible with these findings that involve specific and non-specific aggregation of PC are discussed.
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  • 81
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    Experimental brain research 82 (1990), S. 456-458 
    ISSN: 1432-1106
    Keywords: HRP histochemistry ; Whole-brain preparations ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Subsequent to eye injections of horseradish peroxidase (HRP) ‘whole-brain’ preparations with only the cortex removed were reacted for HRP using tetramethylbenzidine (TMB) as the chromogen and ammonium heptamolybdate (AHM) as a stabilizer. Retinal projections could be photographed and visualized globally coursing across the surface of the thalamus and midbrain. The brains were then sectioned, and when necessary re-reacted, enabling a 3-D reconstruction of retinofugal pathways to be made.
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  • 82
    ISSN: 1432-1106
    Keywords: Sympathetic nerve ; Superior cervical ganglion ; Cerebral arteries ; Wheat germ agglutininhorseradish peroxidase (WGA-HRP) ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary To clarify the projection route and the expansion of the terminal plexus of the sympathetic nerve fibers innervating the cerebral arterial system in rat, we labeled the postganglionic fibers originating in the superior cervical ganglion and traced their entire course by anterograde labeling with wheat germ agglutinin-horseradish peroxidase. Sympathetic innervation of the internal cerebral artery by labeled fibers actually began just at the portion where it enters the intradural space, and innervated it up to the small pial arteries located in the subarachnoid space, but not the intracerebral arterioles. On the main arteries in the circle of Willis, bundles of nerve fibers ran parallel to the long axis of the vessels and branched perpendicularly their terminal twigs with regular intervals to form a rib-structure pattern. On the arterial branches derived from the circle of Willis, a fine nerve bundle and delicate terminal axons formed a meshwork instead of a rib-structure pattern. These observations confirmed the existence of differences in the distribution pattern of the nerve plexus, which strongly affects the strength and quality of vasoconstriction by sympathetic activation in each level of the cerebral arterial system.
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  • 83
    ISSN: 1432-1106
    Keywords: Neural explants ; Catecholaminergic neurons ; Basal ganglia ; Brainstem ; Neural development ; Tyrosine hydroxylase ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Tissue slices of rat ventral mesencephalon (VM), striatum, hippocampus and cerebellum were prepared from late fetal (E21) to 7 day old (P7) rats and cultured for 3 to 60 days by the roller tube technique before they were stained immunocytochemically for tyrosine hydroxylase (TH), a marker of dopaminergic (DA) neurons and fibres. The TH immunoreactive (TH-i), DA neurons retained their morphological in vivo characteristics in the VM slice cultures consisting of the substantia nigra (SN) and the ventral tegmental area (VTA). The general morphology of the described neuronal cell types did not appear to change when the VM slices were cocultured with striatal tissue, a major normal target of the DA neurons, but an extensive innervation of the striatum by TH-i nerve fibres was observed. In co-cultures of VM and hippocampus, a minor target organ of DA fibres, growth of TH-i nerve fibres was observed mainly into the opposing edge of the hippocampal slice. In co-cultures of VM and cerebellum, which is normally devoid of DA fibres, no significant growth of TH-i nerve fibres into the cerebellar slices was observed. Besides suggesting a target orientated growth of ventral mesencephalic DA fibres, the results point to the further use of VM slice cultures in the study of the developmental, plastic and regenerative properties of DA neurons.
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  • 84
    ISSN: 1432-1106
    Keywords: Somatostatin ; NADPH diaphorase ; Deafferentation-somatosensory cortex ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Recent studies in the developing cortex have shown that during the first 2 postnatal weeks somatostatin (SRIF)-containing neurons appear in greater numbers. After this time their numbers decline significantly probably due to cell death (Cavanagh and Parnavelas 1988). In this study we report changes in the distribution of SRIF-labelled cells in the somatosensory cortex of adult rats following unilateral lesions of mystacial vibrissae at birth. Specifically, we observed that the side contralateral to the lesion contained a significantly greater number of labelled cells compared to the ipsilateral side. We suggest that the decline in cell numbers observed during normal development is reduced following early deafferentation.
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  • 85
    ISSN: 1432-1106
    Keywords: Ischemia ; Neuronal death ; Dopamine ; Striatum ; Mesostriatal system ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Transient periods of global cerebral ischemia lead to selective neuronal damage in the striatum. We investigated the effects of unilateral 6-hydroxydopamine lesions of the mesostriatal dopamine (DA) system on the density and distribution of neuronal necrosis in the rat striatum following ischemia induced by bilateral occlusion of the common carotid arteries combined with hypotension. After both 12 and 15 min of ischemia, which caused slight and extensive striatal damage, respectively, there was no difference in the density of neuronal necrosis in the striatum between DA-lesioned and shamoperated animals. We conclude that the DA system alone does not modulate injury following complete cerebral ischemia, but may contribute significantly to damage following conditions such as during hypoglycemia and incomplete cerebral ischemia.
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  • 86
    ISSN: 1432-1106
    Keywords: Mesencephalic trigeminal nucleus ; Astrocytes ; GFAP ; Primary afferent neurons ; Immunocytochemistry ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The arrangement between astrocytes and the primary afferent neurons of the mesencephalic trigeminal nucleus (Me5) was analyzed in a light and electron microscopy immunocytochemistry study using anti-GFAP antibodies. It appears that each Me5 neuron is almost entirely sheathed with astrocytic processes radiating out from two or more astrocytes. Ultrastructural observations confirmed the embracement of Me5 neurons by astrocytic processes that only allowed some synaptic contacts on the neuronal surface. The possible functional significance of this intimate morphological relationship for the mesencephalic trigeminal neurons is discussed.
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  • 87
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    European journal of clinical pharmacology 38 (1990), S. 489-491 
    ISSN: 1432-1041
    Keywords: irtemazole ; dose-response relationship ; pharmacokinetics ; uricosuric drugs ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Irtemazole 12.5 to 50 mg in 6 healthy, normouricaemic subjects caused a maximal decrease in plasma uric acid (after 8 to 12 h) of 46.5%. The uricosuric effect began during the first 60 min after drug administration and it lasted for 7 to 24 h. Renal uric acid excretion returned to its base line value after 8 to 16 h and uric acid clearance after 10.0 to 12.0 h. Doses of irtemazole between 12.5 and 37.5 mg produced a dose-related rise in the uricosuric effect. There was no essential difference between the uricosuric effect of 37.5 mg and 50 mg irtemazole. The D50 dose (that producing a half-maximal effect) was between 16.3 mg and 34.2 mg, (average 24.7 mg). The value of irtemazole in the management of hyperuricaemia and gout remains to be determined.
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  • 88
    ISSN: 1432-1041
    Keywords: ibuprofen ; rheumatoid arthritis ; enantiomer ; stereoselectivity ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary S(+)-, R(−)- or racemic ibuprofen was administered orally to volunteers in doses of 150 mg, 300 mg and 500 mg pure S(+)-, 300 mg pure R(−)- and 600 mg racemic ibuprofen. The pharmacokinetic parameters in humans showed that S(+)-ibuprofen was not inverted to R(−)-ibuprofen, whereas R(−)-ibuprofen was inverted to S(+)-ibuprofen to a variable degree. S(+)-ibuprofen and R(−)-ibuprofen given alone more rapidly reached significantly higher maximal plasma concentrations than after the same doses of the racemic compound. The elimination half-lives and clearance values for all three forms of ibuprofen were comparable. The mean residence time of S(+)-ibuprofen after R(−)- and racemic ibuprofen was significantly longer than after administration of the pure S(+)-enantiomer. Judged by the AUC, the bioavailability of S(+)-ibuprofen was independent of the dose within the range tested. Administration of S(+)-ibuprofen to 6 rheumatic patients showed that the pharmacokinetic behaviour of S(+)-ibuprofen in patients was similar to that found in volunteers. S(+)-ibuprofen proved to be an effective analgesic antirheumatic drug in the dose range 1 to 1.5 g/day.
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  • 89
    ISSN: 1432-1041
    Keywords: rifampicin ; cerebrospinal fluid ; children shunt infections ; adverse effects ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The objectives of this study were to characterize the pharmacokinetics and determine the cerebrospinal fluid concentrations and safety of intravenous rifampin in pediatric patients undergoing shunt placement. Nine patients (mean age 5.6 y) received a single dose of rifampin, 20 mg · kg−1, administered intravenously 1 h prior to surgery. The peak serum concentrations ranged from 13.5–26.7 μg · ml−1; cerebrospinal fluid concentrations ranged from 0.12–3.0 (mean: 1.4) μg · ml−1. The mean total clearance, apparent distribution volume, and elimination half-life were 0.291 · kg−1 · h−1, 1.11 · kg−1, and 2.8 h. The concentrations of rifampin achieved in the cerebrospinal fluid exceeded the minimum inhibitory concentrations by 100-to 1000-fold against Staphylococcus epidermidis. However, 5 of 9 patients developed cutaneous reactions during intravenous rifampin prophylactic therapy. Because of the high frequency of adverse effects and more than adequate rifampin concentrations achieved in the cerebrospinal fluid, rifampin doses lower than that used in this study may be evaluated in future studies.
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  • 90
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    European journal of clinical pharmacology 38 (1990), S. 523-524 
    ISSN: 1432-1041
    Keywords: tolbutamide ; hydroxytolbutamide ; carboxytolbutamide ; urinary excretion ; age ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Tolbutamide (1 g/70 kg) was administered as a single intravenous dose to 31 healthy, non-smoking, drug-free males between 23 and 87 years old and the total amounts of hydroxy and carboxytolbutamide excreted in 24 h were measured. There was a significant decrease in the urinary recovery of both metabolites with age. The reason for these findings is not known at the present time and may be associated with the decrease in creatinine clearance observed in these subjects or other changes in the pharmacokinetics of tolbutamide which are currently being investigated.
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  • 91
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    European journal of clinical pharmacology 38 (1990), S. 499-503 
    ISSN: 1432-1041
    Keywords: 2-mercaptopropionylglycine ; body clearance ; half-life ; pharmacokinetics ; protein binding
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of 2-mercaptopropionylglycine (2-MPG) was studied in ten healthy volunteers after a single i. v. injection of 250 mg (1532 μmol). The total and non-protein-bound concentrations versus time curves were best described by a three-exponential function with terminal half-lives of 55 and 59 h respectively. Body clearance based upon the total concentration was estimated to be 105 and 231 ml/min based on the non-protein-bound 2-MPG. The corresponding values for Vss were 99 l and Vss,n 173 l, and for Vγ485 l and Vγ,n 1121 l respectively. 75% of the dose was excreted in the urine, mainly during the first 6 h after injection. The proportion of non-protein-bound 2-MPG diminished exponentially during the first 15 h and then levelled off at about 30%. There was a nonlinear increase in the non-protein-bound fraction of 2-MPG as the total plasma concentration of the drug increased.
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  • 92
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    European journal of clinical pharmacology 38 (1990), S. 526-527 
    ISSN: 1432-1041
    Keywords: phenytoin ; posture ; pharmacokinetics ; plasma levels
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
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  • 93
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    European journal of clinical pharmacology 38 (1990), S. 579-582 
    ISSN: 1432-1041
    Keywords: d-sotalol ; d,l-sotalol ; pharmacokinetics ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of d-sotalol has been studied in six healthy volunteers given single doses of 0.25, 0.50, 1, 2 mg·kg−1 i.v. and one 100 mg oral dose in comparison with the kinetics of 1 mg·kg−1 i.v. of dlsotalol. There was no significant difference in the disposition of the d-enantiomer and the racemate. The terminal half-life averaged 7.2 h, and the kinetics was linear, with a mean total clearance of 0.13 l·h−1·kg−1. Renal clearance of d-sotalol represented 56 to 77% of total clearance. The absolute systemic availability of oral d-sotalol was close to 100% and the elimination half-life of the oral-d-enantiomer was similar to that of the i.v. form (7.5 h).
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  • 94
    ISSN: 1432-1041
    Keywords: Atenolol ; metoprolol CR ; elderly subjects ; subjective symptoms ; pharmacokinetics ; pharmacodynamics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In a double-blind, randomised, cross-over study, the pharmacokinetic/dynamic effects and subjective symptoms of a new controlled-release (CR) formulation of metoprolol (50 and 100 mg) have been compared with atenolol (50 mg) and placebo in 20 elderly healthy subjects. The metoprolol CR formulation displayed an even plasma concentration-time profile over the dosage interval while atenolol produced a peak at 2–4 h. All three active treatments produced significant β1-blockade at 24 h compared to placebo. Four hours after dose intake, the degree of β1-blockade was significantly greater with conventional atenolol 50 mg than with either dose of metoprolol CR. Subjective well-being was examined with a self-administered questionnaire (MSE-profile), including three dimensions: Contentment, Vitality and Sleep. No significant differences were detected between placebo and either dose of metoprolol CR. At 2 h, following atenolol, a deterioration in Vitality was observed compared to placebo and metoprolol CR 100 mg. At the end of the dosage interval there was no longer any significant difference between the treatments. Perceived leg fatigue during exercise, evaluated 4 h after dosing, was more pronounced during treatment with atenolol than metoprolol CR 50 mg. The results suggest that the metoprolol CR formulation was not associated with significant effects on subjective well-being, whereas atenolol caused a deterioration at the time of the peak plasma concentration of the drug.
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  • 95
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    European journal of clinical pharmacology 38 (1990), S. 587-593 
    ISSN: 1432-1041
    Keywords: prenylamine ; racemic drug ; stereoselectivity ; metabolism ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of S-(+)- and R-(−)-prenylamine was studied in eight healthy volunteers given single and repeated oral doses of the racemic drug. Distinct differences in various pharmacokinetic parameters were found between the S- and R-enantiomer. The maximum plasma concentrations and AUCs of the R-enantiomer exceeded those of the S-enantiomer five-fold; the apparent oral clearance of the S-form was five-times and the renal clearance three-times higher than of the R-form. Acid catalyzed hydrolysis of urine samples released more S-prenylamine, indicating stereoselective glucuronidation of unchanged prenylamine. Plasma protein binding also differed between the two enantiomers, generally with a higher unbound fraction of the S-form, whereas analysis of the bound fractions showed that prenylamine was bound to different plasma proteins with inverse stereoselectivity.
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  • 96
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    European journal of clinical pharmacology 38 (1990), S. 599-603 
    ISSN: 1432-1041
    Keywords: Isradipine ; cirrhosis ; systemic ; calcium antagonist ; aminopyrine breath test ; serum bile acids ; galactose elimination ; pharmacokinetics ; bioavailability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of the dihydropyridine calcium antagonist isradipine has been examined in 8 healthy volunteers, 7 patients with non-cirrhotic chronic liver disease (CLD), and 8 patients with biopsy-proven cirrhosis (CIR). Isradipine was simultaneously given orally (12C 5 mg) and i.v. (13C 1 mg). Systemic availability was significantly increased from 17% and 16% in controls and CLD, respectively, to 37% in CIR. The corresponding systemic clearances averaged 1.1, 0.9 and 0.61 · min−1, the reduction in cirrhotics being significant. Both aminopyrine demethylation capcity, a measure of hepatic microsomal function, and indocyanine green disappearance, a measure of hepatic perfusion, were correlated with the reduction in systemic clearance, and the reduction in oral clearance was correlated with the reciprocal of the serum bile acid concentration. The loss of first-pass extraction should be considered when this calcium antagonist is given perorally in patients with hepatic cirrhosis.
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  • 97
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    European journal of clinical pharmacology 38 (1990), S. 595-598 
    ISSN: 1432-1041
    Keywords: flecainide ; pharmacokinetics ; absorption ; non-parenteral administration ; healthy subjects ; rectal administration
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The absorption kinetics of different pharmaceutical formulations of orally and rectally administered flecainide have been assessed in a cross-over study in 7 healthy volunteers. The subjects received single doses of flecainide after a washout period of at least one week. A tablet, an oral solution, a rectal solution and a 10 min i.v. infusion during 10 min each containing 100 mg flecainide were administered to the subjects in a randomized order. The mean absolute bioavailability was 98%, 78% and 81% for the rectal and oral solutions and the tablet. The lag time after administration of the oral solution was 0.33 h and it was 0.86 h after the tablet and 0.18 h after the rectal solution. The mean time to the peak serum concentration (tmax) after the rectal solution (0.67 h) was shorter than after either the tablet (4 h) or oral solution (1 h). The maximum serum concentration (Cmax) was 0.29 mg · 1−1 after the rectal solution, 0.14 mg · 1−1 after the tablet and 0.17 mg · 1−1 after the oral solution. All the volunteers showed significantly higher serum flecainide concentrations during the first 20 min of the absorption phase after rectal administration of 100 mg flecainide as a solution compared to its oral administration. In conclusion: based on the absolute bioavailability, Cmax, tmax, and lag times, rectal administration of flecainide solution gave a better absorption profile than after oral tablet or solution.
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  • 98
    ISSN: 1432-1041
    Keywords: Cisapride ; pharmacokinetics ; bioavailability ; suppository ; tablet
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The comparative bioavailability of cisapride as a 30 mg suppository and three 5 mg oral tablets was investigated in 12 non-smoking, healthy male volunteers. The two formulations were administered on two separate occasions following an overnight fast, according to a randomized cross-over design. The plasma concentration of cisapride was measured over 48 h after drug administration. The 30 mg suppository exhibited a mean time to the peak plasma concentration of 3.8 h, while the tablets showed a significantly earlier peak time of 1.5 h. The maximum plasma concentration of cisapride after the 30 mg suppository (50.3 ng · ml−1) was significantly lower than after the tablets (74.3 ng · ml−1). The AUCs following the two treatments did not differ significantly from each other. The comparative bioavailability of the 30 mg cisapride suppository in relation to the three 5 mg oral tablets was 85%, with a 95%-confidence interval of 67% to 102% (not adjusted for dose). Normalizing the mean AUC by dose, the relative bioavailability of the suppository was 43% of that of the tablet. The elimination half-life of cisapride was not significantly different following the administration of the two formulations (9.3 h for the suppository and 9.8 h for the tablet).
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  • 99
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    European journal of clinical pharmacology 39 (1990), S. 193-194 
    ISSN: 1432-1041
    Keywords: methocarbamol ; haemodialysis ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary We determined plasma methocarbamol concentrations over 24 h following a 1.5 g methocarbamol dose (off-dialysis day) to 8 chronic haemodialysis patients and compared these results to those from 17 healthy male volunteers. The harmonic mean elimination half-life was similar between the two groups, 1.24 and 1.14 h, respectively. tmax and the weight-adjusted Cmax were 1.1 h and 27.0 mg · m−1 for haemodialysis patients and 1.1 and 23.1 mg · l−1 for normals. Relative systemic availability was assessed by comparing weight-normalized AUC × k10 products. These results indicate no significant differences with respect to methocarbamol absorption, with the relative systemic availability in patients being 113%. These data suggest that absorption and elimination of methocarbamol is similar between normal subjects and patients undergoing maintenance haemodialysis.
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  • 100
    ISSN: 1432-1041
    Keywords: Hypertension ; perindopril ; hydrochlorothiazide ; ACE inhibition ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacodynamic effects and acceptability of perindopril (4 mg daily) and hydrochlorothiazide (25 mg daily) given alone or in combination for 1 month were investigated in a double-blind, placebo controlled, parallel group study. The pharmacokinetics of perindopril and its active metabolite perindoprilat and the time course of angiotensin converting enzyme inhibition were studied for 72 h following the last dose of treatment in the two appropriate groups. Similar decreases in blood pressure were seen 24 h after the last dose of perindopril or hydrochlorothiazide (11/7 mm Hg supine) given alone at these doses. The effect of these drugs given together was additive on diastolic blood pressure and synergistic on systolic blood pressure (24.5/12.6 mm Hg supine) taking into account the placebo response. The significant increase in plasma renin activity produced by perindopril alone was potentiated by concurrent administration of hydrochlorothiazide. The formation of perindoprilat was slightly reduced in the group also receiving hydrochlorothiazide and there was a very small reduction in ACE inhibition in this group. Perindopril, whether given alone or in combination with hydrochlorothiazide, was well tolerated and produced no clinically significant change in routine haematology or serum biochemistry. The additive or synergistic effects of perindopril and hydrochlorothiazide on blood pressure must be due to their complementary physiological actions and not to a pharmacokinetic interaction.
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