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  • 1990-1994  (1,493)
  • 1980-1984  (1,041)
  • Rat  (1,531)
  • pharmacokinetics  (1,001)
  • Nuclear reactions
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Year
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  • 1
    Electronic Resource
    Electronic Resource
    Effects of flezelastine and its enantiomers on LPS-induced IL-1β generationin vitro and LPS-induced pyrexiain vivo (1994)
    Springer
    Inflammation research 41 (1994), S. 99-100 
    Details
    ISSN: 1420-908X
    Keywords: Lipopolysaccharide ; Interleukin 13 ; Pyrexia ; Flezelastine ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The effects of the novel antiasthmatic/antiallergic compound flezelastine on LPS-induced actions were investigatedin vitro andin vivo. In monocytes, IL-1β generation stimulated by LPS was inhibited dose dependently.In vivo, LPS-induced fever in rats, which is at least partly driven by the release of IL-1β, was also inhibited by flezelastine. These findings suggest that flezelastine inhibits IL-1 synthesis and/or releasein vitro andin vivo.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01986405
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  • 2
    Electronic Resource
    Electronic Resource
    Comparative dose-related time-action profiles of glibenclamide and a new non-sulphonylurea drug, AG-EE 623 ZW, during euglycaemic clamp in healthy subjects (1994)
    Springer
    Diabetologia 37 (1994), S. 703-707 
    Details
    ISSN: 1432-0428
    Keywords: Glibenclamide ; glyburide ; sulphonylurea ; compounds ; AG-EE 623 ZW ; dose-response ; time-action profiles ; pharmacokinetics ; glucose clamp technique
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Insulin and glucose responses to glibenclamide were studied in comparison to a novel non-sulphonylurea drug (AG) by means of the euglycaemic clamp technique. Nine fasting male subjects were connected to a Biostator and 1.75, 3.5 or 7.0 mg glibenclamide or 1.0, 2.0 or 4.0 mg AG were given and blood glucose concentrations were clamped at 10% below basal values. Glucose infusion rates were registered over 10 h after administration of the tablet. Maximal glucose infusion rates after glibenclamide were 40% higher compared to AG (1.75 vs 1.0 mg, 3.5 vs 2.0 mg, 7.0 vs 4.0 mg, respectively) and were reached after 3–3.5 h for all doses. After glibenclamide, area under the glucose infusion curves and maximal incremental serum insulin responses were higher by 25–40% and by 30% compared to AG when low, medium and high doses of each drug were tested. However, a linear dose relationship was obtained for both drugs when the glucose infusion rate was plotted against the area under the insulin curve. In fact, both drugs were equipotent on a molecular weight basis. The hypoglycaemic index of both drugs (integrated glucose infusion rate divided by integrated insulin release) expressed per μmol of drug revealed a dose-dependent and parallel inverse curvilinear relation to increasing doses. This methodological approach allowed us to quantify and compare the metabolic effects of oral hypoglycaemic agents under standardised experimental conditions.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00417695
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  • 3
    Electronic Resource
    Electronic Resource
    Effect of insulin concentration, subcutaneous fat thickness and skin temperature on subcutaneous insulin absorption in healthy subjects (1994)
    Springer
    Diabetologia 37 (1994), S. 377-380 
    Details
    ISSN: 1432-0428
    Keywords: Diabetes mellitus ; pharmacokinetics ; insulin absorption ; metabolic control ; skin temperature
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Subcutaneous insulin absorption kinetics were assessed in 50 healthy study subjects (21 female, 29 male; age 26±3 years, BMI 22.5±1.8 kg/m2; mean±SD) during 45 min after periumbilical injection of soluble human U40- or U100-insulin (0.15 IU/kg). Subcutaneous fat thickness was measured by ultrasound, and skin temperature at the injection site was registered. Serum insulin concentrations increased within 30 min from basal values of 37±15 to 140±46 pmol/l after U40-insulin and from 36±10 to 116±37 pmol/l after U100-insulin (p〈0.001). After 45 min serum insulin concentrations were 164±43 pmol/l with U40-insulin and 128±35 pmol/l with U100-insulin (p〈0.001). Decline in blood glucose levels and suppression of C-peptide were comparable. The serum insulin levels reached 30 and 45 min after U40- and U100-insulin injection were positively correlated with skin temperature (p〈0.0008), and negatively correlated with subcutaneous fat thickness (p〈0.009). In conclusion, the lower insulin concentration of U40-insulin, higher skin temperature, and a thinner subcutaneous fat tissue at the injection site are associated with accelerated and enhanced subcutaneous insulin absorption.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00408474
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  • 4
    Electronic Resource
    Electronic Resource
    Postnatal development of neuropeptide Y- and calcitonin gene-related peptide-immunoreactive nerves in the rat urinary bladder (1994)
    Springer
    Anatomy and embryology 189 (1994), S. 361-373 
    Details
    ISSN: 1432-0568
    Keywords: Postnatal development ; Neuropeptide Y ; Calcitonin gene-related peptide ; Urinary bladder ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The postnatal development of neuropeptide Y- and calcitonin gene-related peptide-immunoreactive (NPY-IR and CGRP-IR) nerve fibers in the rat urinary bladder was investigated using whole-mount preparations and cryostat sections. In newborn and 3-day-old rats, many NPY-IR nerve fibers were observed in the subserous and muscle layers. Many NPY-IR nerve cell bodies clustered at branching points of the subserous nerve bundles. Within 4 weeks after birth, these cell bodies drastically decreased in number and spread along the bundles, although the number of NPY-IR nerve fibers increased moderately. In contrast, CGRP-IR nerve fibers in newborn and 3-day-old rats were less developed, and no CGRP-IR nerve cell body was observed in any rat. However, CGRP-IR nerve fiber distribution in the urinary tissues conspicuously increased within 4 weeks after birth. Especially, an increase of the infraepithelial fibers showing a meshwork appearance was prominent in the fundus and corpus of the bladder. The infra- and intraepithelial CGRP-IR nerve meshwork of the ventral wall was more dense than that of the trigone. At 4 weeks, NPY-IR and CGRP-IR nerves were similar to those of the adult rat (8–12 weeks old). The present study suggests a correlation between the development of the peripheral nervous system in the urinary bladder and maturation of micturition behavior in the rat.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00190591
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  • 5
    Electronic Resource
    Electronic Resource
    Fiber composition of the lateral plantar and superficial peroneal nerves in the rat foot (1994)
    Springer
    Anatomy and embryology 189 (1994), S. 393-399 
    Details
    ISSN: 1432-0568
    Keywords: Rat ; Myelinated axons ; C-fibers ; Skin ; Electron microscopy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract This study examines the fiber composition of two nerves projecting to the rat hindpaw: the lateral plantar nerve (LPN), which innervates plantar glabrous skin and some plantar muscles, and the foot branch of the superficial peroneal nerve (fSPN), which projects to dorsal hairy skin. The LPN contains 872 (33%) myelinated axons with a size range of 1–7 μm and a peak at 4 μm. Some 200 of the myelinated axons are muscle efferents. There are 1,969 (67%) C-fibers. After neonatal capsaicin treatment, the number of C-fibers in the LPN is 61% below the normal level, but it is not significantly different from control levels after chemical sympathectomy with guanethidine. The fSPN is composed of 470 (20%) myelinated axons with a size range similar to that in the LPN. Virtually all myelinated fibers are sensory. There are 1,791 (80%) C-fibers. In neonatally capsaicin-treated animals, the occurrence of C-fibers is 65% below control levels. In chemically sympathectomized animals, the number of C-fibers in the fSPN is normal. This description of the fiber composition of the LPN and the fSPN in the rat provides a basis for future experimental studies.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00185434
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  • 6
    Electronic Resource
    Electronic Resource
    Parcellation of cortical areas by in situ hybridization for somatostatin mRNA in the adult rat: frontal, parietal, occipital, and temporal regions (1994)
    Springer
    Anatomy and embryology 190 (1994), S. 389-398 
    Details
    ISSN: 1432-0568
    Keywords: Neuropeptides ; Visual cortex ; Somatosensory cortex ; Auditory cortex ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The expression of somatostatin mRNA within the neocortex of the rat was examined by in situ hybridization with an alkaline phosphatase-labeled probe. We sought to determine whether parcellation of the neocortex could be based upon the number and laminar location of the hybridized cells. Our investigation demonstrated that the boundaries of the neocortical areas can be determined by the distribution pattern of neurons expressing somatostatin mRNA. Few hybridized cells were located within layer IV, and this sparsity of cells within their wide granular layer marked the primary sensory areas. The occipital region was stratified, with insensely labeled cells in layers II/III and VI and faintly labeled cells in layer V. The parietal region carried a similar stratification, but more space between intensely labeled cells in layers III and V and between layers V and VI gave the region a three-tiered appearance. The temporal region displayed intensely labeled cells dispersed throughout layers III and VI and many in layer V as well as those faintly labeled without any breaks between the laminae. The distribution of the cells hybridized for somatostatin mRNA formed two configurations within the frontal region. It was difficult to identify any lamination in the first area, whereas the second area demonstrated a stratification reminiscent of the parietal region, but with only two tiers. The conclusion of the investigation is that in situ hybridization for somatostatin mRNA provides an exceptional means by which the areal boundaries within the neocortex may be drawn.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00187297
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  • 7
    Electronic Resource
    Electronic Resource
    Distribution of acetylcholinesterase activity in the rat embryonic heart with reference to HNK-1 immunoreactivity in the conduction tissue (1994)
    Springer
    Anatomy and embryology 190 (1994), S. 367-373 
    Details
    ISSN: 1432-0568
    Keywords: Acetylcholinesterase ; HNK-1 ; Heart ; Morphogenesis ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Acetylcholinesterase (AChE) activity was topographically investigated in the presumptive cardiac conduction tissue regions visualized by HNK-1 immunoreactivity in rat embryos, and AChE-positive cells were examined with the electron microscope. On embryonic day (ED) 14.5, when HNK-1 was most intensely visualized, AChE activity could not be detected enzyme-histochemically in the conduction tissue regions, except in the ventricular trabeculae and part of the AV node. On ED 16.5, however, the AChE activity was clearly demonstrated in some parts of the developing conduction tissue. One exception was the AV node region, where an AChE-positive area was in close proximity to an area showing HNK-1 immunoreactivity but did not overlap. Furthermore, AChE activity was demonstrated predominantly in the ventricular trabeculae, including cardiac myocytes, but was rather weak in the atrium. With the electron microscope, AChE reaction products were observed predominantly intracellulary in both developing conduction tissue cells and developing ordinary myocytes, and no reactivity was found in neuronal components. From ED 18.5 until birth, both AChE activity and HNK-1 immunoreactivity faded away in the conduction tissue. Thus, transient AChE activity in the embryonic heart seems to be different from the developing adult form and may be related to a morphogenetic function in embryonic tissues, as proposed by other authors.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00187294
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  • 8
    Electronic Resource
    Electronic Resource
    The effect of focal cerebral cooling on perinatal hypoxic-ischemic brain damage (1994)
    Springer
    Acta neuropathologica 87 (1994), S. 598-604 
    Details
    ISSN: 1432-0533
    Keywords: Ischemia ; Hypothermia ; Brain ; Immature ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract We describe a method of focal cooling of the head and its effects on hypoxic-ischemic cerebral damage in neonatal rat. Focal cooling of the head was obtained by positioning a catheter under the scalp ipsilateral to the ligated common carotid artery and by running cold water through the catheter during 2 h of systemic hypoxia. Hypoxia was produced in neonatal rats by breathing 8% oxygen for 2 h in a 37°C chamber. Animals underwent focal cooling with ipsilateral scalp temperatures ranging from 22°C to 35°C. Temperature recordings from the ipsilateral scalp, cerebral hemisphere (dorsal hippocampus) and core (rectal) were obtained. The results suggest that the method is effective in cooling of brain and also to a lesser extent in lowering of the core temperature. At a mean scalp temperature of 28°C, mean hippocampal temperature in hypoxic rat was 29.5°C and mean core temperature in hypoxic rat was 32.8°C. At a lower scalp temperature of 22°C, mean hippocampal temperature in hypoxic rat was 24.7°C and mean core temperature was 31.3°C. Neuropathologic examination 3–4 days following hypoxia-ischemia showed that focal cooling with a scalp temperature of lower than 28°C completely protected from brain damage, and that there was a trend towards greater damage with higher scalp temperatures.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00293321
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  • 9
    Electronic Resource
    Electronic Resource
    Permanent increase of immunocytochemical reactivity for γ-aminobutyric acid (GABA), glutamic acid decarboxylase, mitochondrial enzymes, and glial fibrillary acidic protein in rat cerebral cortex damaged by early postnatal hypoxia-ischemia (1994)
    Springer
    Acta neuropathologica 87 (1994), S. 612-627 
    Details
    ISSN: 1432-0533
    Keywords: Hypoxia-ischemia ; Rat ; Perinatology ; Cerebral cortex ; Immunocytochemistry
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract A former study indicated that hypoxicischemic encephalopathy in rat sustained during early postnatal life may result in permanent epileptic activity in the baseline electroencephalogram. We, therefore, investigated whether the presumed higher firing frequency and metabolic activity of neurons in such hypoxia-damaged cortical areas would be reflected by an enhanced light microscopic immunoreactivity of γ-aminobutyric acid (GABA), the two isoforms of glutamic acid decarboxylase (GAD67 and GAD65), the mitochondrial enzymes cytochrome c oxidase and ATP synthase, and/or glial fibrillary acidic, protein (GFAP). To that end rat pups, 12–13 days of age, were unilaterally exposed to hypoxic-ischemic conditions and, after a survival period of 2 and 61/2 months, respectively, killed by perfusion fixation. After dissection of the brain, coronal vibratome sections of animals showing cortical damage were immunostained for the presence of the abovementioned antigens. Subsequent qualitative analysis revealed that the surroundings of cortical infarctions were unambiguously characterized by a disordered neural network containing numerous nerve cells, fibers and/or endings showing an enhanced immunoreactivity for GABA, both isoforms of glutamic acid decarboxylase, and cytochrome c oxidase and ATP synthase, while the astrocytes showed an enhanced immunoreactivity for GFAP. The diverse patterns of enhanced immunoreactivity suggested, furthermore, a wider low-to-high range of metabolic activities in both excitatory and inhibitory neurons.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00293323
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  • 10
    Electronic Resource
    Electronic Resource
    Permanent increase of immunocytochemical reactivity for g-aminobutyric acid (GABA), glutamic acid decarboxylase, mitochondrial enzymes, and glial fibrillary acidic protein in rat cerebral cortex damaged by early postnatal hypoxia-ischemia (1994)
    Springer
    Acta neuropathologica 87 (1994), S. 612-627 
    Details
    ISSN: 1432-0533
    Keywords: KeyWordsHypoxia-ischemia ; Rat ; Perinatology Cerebral cortex ; Immunocytochemistry
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract A former study indicated that hypoxic-ischemic encephalopathy in rat sustained during early postnatal life may result in permanent epileptic activity in the baseline electroencephalogram. We, therefore, investigated whether the presumed higher firing frequency and metabolic activity of neurons in such hypoxia-damaged cortical areas would be reflected by an enhanced light microscopic immunoreactivity of γ-aminobutyric acid (GABA), the two isoforms of glutamic acid decarboxylase (GAD67 and GAD65), the mitochondrial enzymes cytochrome c oxidase and ATP synthase, and/or glial fibrillary acid, protein (GFAP). To that end rat pups, 12–13 days of age, were unilaterally exposed to hypoxic-ischemic conditions and, after a survival period of 2 and 6--e2--12 months, respectively, killed by perfusion fixation. After dissection of the brain, coronal vibratome sections of animals showing cortical damage were immunostained for the presence of the above-mentioned antigens. Subsequent qualitative analysis revealed that the surroundings of cortical infarctions were unambiguously characterized by a disordered neural network containing numerous nerve cells, fibers and/or endings showing an enhanced immunoreactivity for GABA, both isoforms of glutamic acid decarboxylase, and cytochrome c oxidase and ATP synthase, while the astrocytes showed an enhanced immunoreactivity for GFAP. The diverse patterns of enhanced immunoreactivity suggested, furthermore, a wider low-to-high range of metabolic activities in both excitatory and inhibitory neurons.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00293323
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  • 11
    Electronic Resource
    Electronic Resource
    The effect of focal cerebral cooling on perinatal hypoxic-ischemic brain damage (1994)
    Springer
    Acta neuropathologica 87 (1994), S. 598-604 
    Details
    ISSN: 1432-0533
    Keywords: KeyWordsIschemia ; Hypothermia ; Brain Immature ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract We describe a method of focal cooling of the head and its effects on hypoxic-ischemic cerebral damage in neonatal rat. Focal cooling of the head was obtained by positioning a catheter under the scalp ipsilateral to the ligated common carotid artery and by running cold water through the catheter during 2 h of systemic hypoxia. Hypoxia was produced in neonatal rats by breathing 8   % oxygen for 2 h in a 37 °C chamber. Animals underwent focal cooling with ipsilateral scalp temperatures ranging from 22 °C to 35 °C. Temperature recordings from the ipsilateral scalp, cerebral hemisphere (dorsal hippocampus) and core (rectal) were obtained. The results suggest that the method is effective in cooling of brain and also to a lesser extent in lowering of the core temperature. At a mean scalp temperature of 28 °C, mean hippocampal temperature in hypoxic rat was 29.5 °C and mean core temperature in hypoxic rat was 32.8 °C. At a lower scalp temperature of 22 °C, mean hippocampal temperature in hypoxic rat was 24.7 °C and mean core temperature was 31.3 °C. Neuropathologic examination 3–4 days following hypoxia-ischemia showed that focal cooling with a scalp temperature of lower than 28 °C completely protected from brain damage, and that there was a trend towards greater damage with higher scalp temperatures.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00293321
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  • 12
    Electronic Resource
    Electronic Resource
    Carotid artery stenosis and tachyarrhythmias: regional cerebral blood flow during high-rate ventricular pacing after one vessel occlusion in rats (1994)
    Springer
    Journal of molecular medicine 72 (1994), S. 775-781 
    Details
    ISSN: 1432-1440
    Keywords: Cerebral blood flow ; Carotid stenosis ; Microspheres ; Ventricular tachycardia ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The aim of the present study was to investigate the effect of hypotensive tachycardias on cerebral blood flow (CBF) in the presence of significant carotid stenosis. The experiments were performed in 57 spontaneously breathing rats during arterial normoxia and normocapnia anesthetized with thiobarbital. CBF was determined with radio-labeled microspheres during control conditions (normofrequent sinus rhythm, normotension; group A; n = 15), during high-rate left ventricular pacing (660–840 ppm) at normotension (group B1; n = 13), borderline hypotension (group B2; n = 15) and severe hypotension (group B3; n = 7). In addition, CBF measurements were performed during borderline hypotension induced by hemorrhage (group C; n = 7). Global CBF was 1.09 ± 0.29 ml g−1 min−1 in group A, 0.93 ± 0.40 in group B1, 0.68 ± 0.31 in group B2 (P 〈 0.05 vs. A), 0.42 ± 0.16 in group B3 (P 〈 0.05 vs. A) and 0.83 ± 0.2 in group C. The highest CBF values were found in the cerebellum (A; 1.43 ± 0.5 ml g−1 min−) and the lowest in the postocclusive tissue of the ipsilateral hemisphere (A; 0.74 ± 0.2 ml g−1 min−1). In all groups a 15% mean CBF reduction in the right hemispherical cerebrum in comparison to the left hemisphere was observed (P 〈 0.01). In contrast, hemispherical CBF of the cerebellum did not differ. The CBF blood pressure relationship shifted to lower CBF values, the threshold of CBF regulation shifted to higher blood pressure values in the tissue regions distal to the occluded vessel during hypotensive tachycardias. One carotid artery occlusion and high rate ventricular pacing seem to be a reliable model for quantifying cerebral hemodynamics during arrhythmias in the presence of carotid stenoses. Using this experimental approach it was demonstrated that hypotensive tachycardias and obstructions within the ectracranial carotid vascular bed such as arterial vessel stenoses and occlusions have an additive effect on CBF reduction.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00180546
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  • 13
    Electronic Resource
    Electronic Resource
    Representation of the body in the lateral striatum of the freely moving rat: single neurons related to licking (1994)
    Springer
    Experimental brain research 98 (1994), S. 163-167 
    Details
    ISSN: 1432-1106
    Keywords: Licking ; Oral behavior ; Electrophysiology ; Striatum ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract This study examined the relationship of single-neuron activity (n = 739), recorded from the lateral striatum of freely moving rats, to oral movements involved in licking single drops of liquid. Certain neurons (n = 74) fired specifically in relation to licking. Their firing rates increased during licking, but remained near zero in the absence of licking, throughout a full sensorimotor examination of the remainder of the orofacial area and all other body parts. Another category of neurons (n = 17) fired during licking but also fired in the absence of licking, during one or more other orofacial sensorimotor function(s). Lick-related neurons were located in the lateral striatum, throughout the entire anterior-posterior range studied (from +1.5 to -1.5 mm anterior-posterior, A-P, bregma = 0). Summed over the full A–P range, they were located significantly ventral to representations of the trunk and limbs. These findings extend the characterization of the somatotopic organization exhibited by lateral striatal neurons in the rat, to include representation of oral functions, consistent with converging evidence regarding the functional organization of the striatum.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00229122
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  • 14
    Electronic Resource
    Electronic Resource
    Increase of basic fibroblast growth factor (bFGF, FGF-2) messenger RNA and protein following implantation of a microdialysis probe into rat hippocampus (1994)
    Springer
    Experimental brain research 98 (1994), S. 229-237 
    Details
    ISSN: 1432-1106
    Keywords: In vivo microdialysis ; Astrocytic reaction ; Gliosis ; Brain lesion ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract In vivo microdialysis is an established tool for sampling extracellular fluid compartments. However, microdialysis faces the problem that the implantation of the probe damages the microenvironment from which measurements are derived. In this study, we examined the expression of basic fibroblast growth factor mRNA and protein at the cellular level after implantation of a microdialysis probe into the dorsal hippocampus and found that 8 h after inserting the probe bFGF mRNA was markedly increased in a relatively large area centered around the probe, involving both the dorsal hippocampus and the overlying cerebral cortex, as revealed by radioactive in situ hybridization. Using nonradioactive in situ hybridization with digoxigenin-labelled riboprobes, combined with immunohistochemistry for glial fibrillary acidic protein we demonstrated that bFGF mRNA was exclusively increased in astrocytes at the probe insertion site. Using immunohistochemistry we also found that bFGF-like immunoreactivity was increased after implantation of the probe close to the lesion site, as shown by an increased number of bFGF immunoreactive nuclear glial profiles. These results provide evidence that the implantation of a microdialysis probe into the brain induces activation of bFGF gene expression in astrocytes associated with nuclear bFGF-like immunoreactivity. We conclude that lesion-induced effects have to be considered when evaluating microdialysis data, and that mechanical trauma to the brain will activate astroglial trophism, as seen from the increased density of astroglial profiles demonstrating bFGF mRNA and protein levels.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00228411
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  • 15
    Electronic Resource
    Electronic Resource
    Unilateral ablation of the frontal eye field of the rat affects the beating field of ocular nystagmus (1994)
    Springer
    Experimental brain research 98 (1994), S. 391-400 
    Details
    ISSN: 1432-1106
    Keywords: Optokinetic nystagmus ; Vestibulo-ocular reflex ; Frontal eye field ; Hemineglect ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Spontaneous saccadic orientation and compensatory eye movements in response to optokinetic and vestibular velocity steps were studied in head-restrained, pigmented rats before and 1–2 weeks after unilateral ablation of the frontal eye field (FEF). One group of rats (n=5) received a deep lesion and another group of rats (n=4) received a superficial lesion of the left FEF. Postoperative response parameters such as the duration of slow buildup of eye velocity, the steady state velocity gain, the duration of optokinetic afternystagmus and of per- and postrotatory vestibular nystagmus were similar in the two groups of rats and did not differ from preoperative values measured in the same individuals. Superimposed upon these velocity components of nystagmus was a transient orienting response that expressed itself by a shift of the beating field of nystagmus in quick phase direction (gaze shift). The amplitudes of this gaze shift in quick phase direction were asymmetric in rats with a deep FEF lesion. Gaze shift amplitudes toward the side of the lesion were significantly enhanced and gaze shift amplitudes toward the intact side were significantly reduced. Similar asymmetries were observed in the distribution of spontaneous orienting movements of these rats in the light. Spontaneous saccadic eye movements of the same animals in darkness, however, were symmetric in amplitude to either side. These deficits suggest a partial sensory hemineglect after a deep unilateral lesion of the FEF and an involvement of this structure in the selective attention for targets in visual space. Thus the FEF orients the gaze at rest by means of saccades toward points of interest and during simulated circular locomotion by means of a shift of the beating field of nystagmus toward the visual sector that will be approached next.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00233977
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  • 16
    Electronic Resource
    Electronic Resource
    The effect of hyperthermic treatment on electroencephalographic recovery after interruption of respiration in rats (1994)
    Springer
    Experimental brain research 99 (1994), S. 431-434 
    Details
    ISSN: 1432-1106
    Keywords: Hyperthermic treatment ; Apneic hypoxia ; Electroencephalogram ; Heat-shock protein ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Electroencephalography (EEG) was utilized for investigating the effect of hyperthermia followed by apneic hypoxia in rats. They were heated whole-bodily to 41° C for 15 min under the control of an artificial rodent ventilator, after drug-induced generalized paralysis. A transcutaneous oxygen saturation monitor was applied to detect the hypoxic condition. EEG was monitored with bipolar needle electrodes. The 72-kDa heatshock protein (HSP72) in brain was analyzed by sodium dodecyl sulfate-polyacrylamide electrophoresis, followed by immunostaining with an anti-HSP72 antibody. There was no difference in the time interval from onset of apneic hypoxia to flat EEG between the hyperthermic and control groups, but cortical electrical activity appeared earlier in the hyperthermia group than the control group, after 90 s of ventilation interruption. The cardiac function did not change in the two groups. The HSP72 synthesis significantly increased in the brain of the rats with hyperthermic treatment.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00228979
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  • 17
    Electronic Resource
    Electronic Resource
    Differentiation of hypothalamic GABAergic neurons in vitro: absence of effects of sex and gonadal steroids (1994)
    Springer
    Experimental brain research 99 (1994), S. 435-440 
    Details
    ISSN: 1432-1106
    Keywords: GABA ; Uptake ; Sexual differentiation ; Cell culture ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The inhibitory neurotransmitter gamma-aminobutyric acid (GABA) is involved in the control of sexually dimorphic brain functions, such as pituitary secretion and reproductive behavior. Hypothalamic GABAergic systems in vivo exhibit sexually dimorphic functional properties. Sexual dimorphisms in the rat brain are currently thought to be brought about by the organizational influence of gonadal steroids during the perinatal developmental period. The present study is concerned with the question of whether developing hypothalamic GABAergic neurons are primary targets of sex hormones. Since it is impossible to distinguish direct from indirect effects of experimental manipulations of the hormonal environment of the in vivo brain, sex-specific primary cultures raised from embryonic day 14 rat diencephalon and cultured for up to 8 days in vitro (DIV) were used as a model system. Effects of sex steroids were investigated on high affinity uptake of [3H]GABA. GABA transport was already mature at 3 DIV. [3H]GABA uptake was sensitive to inhibition by nipecotic acid and the transmitter was taken up by high affinity transport (K m=15.2 μM). Immunocytochemical preparations demonstrated extensive networks of GABA-immunoreactive fibers at 8 DIV. Concomitantly with the outgrowth of neurites, there was a marked increase in maximum uptake velocity (Vmax). No differences could be detected regarding cell numbers or uptake kinetics between cultures from male and female donors. Neither cell numbers nor GABA uptake were affected by short- and long-term treatment with estradiol-17β or testosterone. It appears that hypothalamic GABAergic neurons in vitro do not develop sex differences in cell numbers or GABA transport. Both parameters, which otherwise have proved to be good indicators of sexual differentiation of cultured neurons, are also unaffected by sex steroids. These results suggest that sex differences in GABAergic transmission seen in the developing and adult rat in vivo are generated by additional factors, such as afferent or efferent connections with other sexually dimorphic neurons.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00228980
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  • 18
    Electronic Resource
    Electronic Resource
    Therapeutic effects of nilvadipine on rat focal cerebral ischemia (1994)
    Springer
    Experimental brain research 99 (1994), S. 1-6 
    Details
    ISSN: 1432-1106
    Keywords: Nilvadipine ; Ca2+ entry blocker Focal cerebral ischemia ; Therapeutic effect ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The present study was conducted to invetigate the therapeutic effects of nilvadipine, a Ca2+ entry blocker, on rat focal cerebral ischemia. Under halothane anesthesia, a 3-0 nylon thread was introduced into the neck internal carotid artery to occlude the left middle cerebral artery. Either nilvadipine (3.2 mg/kg) or vehicle was administered subcutaneously 1, 2, 3, 4, 5 and 6 h following the occlusion (groups 1–6, respectively). Twenty-four hours after the occlusion, the percentage infarct volumes in nilvadipine-treated animals in groups 1–3 (21±11%, 24±11%, and 26±7%, respectively) were smaller than those in the respective control groups (36±5%, 35±3%, and 35+3%; P〈0.05). Compared with controls, the infarct size of the periphery of the fronto-parietal cortex decreased in nilvadipine-treated animals. The results indicate that nilvadipine decreases the size of infarction when administered up to 3 h after an ischemic insult. Thus, nilvadipine can be considered a potential therapeutic agent for acute focal cerebral ischemia, and may be clinically useful in stroke patients.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00241406
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  • 19
    Electronic Resource
    Electronic Resource
    Once daily dosing of netilmicin in neonatal and pediatric intensive care (1994)
    Springer
    Intensive care medicine 20 (1994), S. 365-367 
    Details
    ISSN: 1432-1238
    Keywords: Netilmicin ; Once daily dosing ; Neonatal/pediatric intensive medicine ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Objective To examine a once daily dosing regimen of netilmicin in critically ill neonates and children. Design and setting Open, prospective study on 81 antibiotic courses in 77 critically ill neonates and children, hospitalized in a multidisciplinary pediatric/neonatal intensive care unit. For combined empiric therapy (aminoglycoside and beta-lactam), netilmicin was given intravenously over 5 min once every 24 h. The dose ranged from 3.5–6 mg/kg, mainly depending upon gestational and postnatal age. Peak levels were determined by immunoassay 30 min after the second dose and trough levels 1 h before the third and fifth dose or after adaptation of dosing. Results All peak levels (n=28) were clearly above 12 μmol/l (mean 22, range 13–41 μmol/l). Eighty-nine trough levels were within desired limits (〈4 μmol/l) and 11 (11%) above 4 μmol/l, mostly in conjunction with impaired renal function. Conclusions Optimal peak and trough levels of netilmicin can be achieved by once daily dosing, adapted to gestational/postnatal age and renal function.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01720910
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  • 20
    Electronic Resource
    Electronic Resource
    Metabolism of a glucuronide conjugate of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone in rats (1994)
    Springer
    Archives of toxicology 69 (1994), S. 14-17 
    Details
    ISSN: 1432-0738
    Keywords: Key words Tobacco-specific nitrosamine ; 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone ; [4-(Methylnitrosamino)-1-(3-pyridyl)but-1-yl]- β-O-d-glucosiduronic acid ; Rat ; Urine ; Metabolism
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Besides 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), [4-(methylnitrosamino)-1-(3-pyridyl)but-1-yl]-β-O-d-glucosiduronic acid (NNAL-Glu) is another important metabolite of the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) which has been detected in the urine of tobacco users and non-smokers heavily exposed to sidestream cigarette smoke. In order to evaluate the toxicological significance of NNAL-Glu formation and excretion, the metabolism of [5-3H]-NNAL-Glu was studied in rats. Five male F344 rats were administered 3.7 mg/kg [5-3H]-NNAL-Glu by i.v. injection and the metabolites in urine analysed by HPLC. More than 90% of the radioactivity was excreted in urine within the first 24 h. Unchanged NNAL-Glu accounted for 81.2±3.1% of the total radioactivity; the remaining part of the dose appears to be deconjugated resulting in the urinary excretion of NNAL (3.6±1.7%) and its α-hydroxylation (11.5±2.2%) and N-oxidation (3.6±1.6%) products. The presence of α-hydroxylation products of NNAL-Glu in urine suggests that this NNK metabolite may be activated in vivo to carcinogenic intermediates.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002040050130
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  • 21
    Electronic Resource
    Electronic Resource
    Regulation of dopamine levels in intrastriatal grafts of fetal mesencephalic cell suspension: an in vivo voltammetric approach (1994)
    Springer
    Experimental brain research 102 (1994), S. 10-20 
    Details
    ISSN: 1432-1106
    Keywords: Dopamine ; Striatum ; Ventral mesencephalic grafts ; Voltammetry ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract An in vivo voltammetric technique was used to monitor dopamine (DA) release in the 6-hydroxydopamine (6-OHDA)-lesioned rat striatum reinnervated by grafts of ventral mesencephalon containing DA neurons. Extracellular levels of DA were measured during the administration of D1 or D2 DA receptor antagonists. In addition, changes in DA levels induced by agonists and antagonists of excitatory amino acid (EAA) receptors were studied to verify the possible existence of a host glutamatergic control on the grafted DA cells in the ‘transplanted’ rats. Two months after the grafts were performed, the voltammetric signal measured under baseline conditions in the grafted striata was found to be almost similar to that recorded on the contralateral control side. Likewise, in another group of transplanted rats, the turnover of the amine, as expressed by the DOPAC/DA tissue level ratio, was found to have become “normalized” after grafting, compared with the lesion-only group. The increase in the voltammetric signal observed after administering the D2 antagonist sulpiride (100 mg/kg i.p.) was lower in the grafted striata than on the contralateral side, however. This suggests that some D2 autoreceptor subsensitivity may have helped to maintain the baseline level of dopaminergic transmission. Adaptive processes of this kind might compensate for the partial DA reinnervation of the host striatum found to occur on the basis of the tyrosine hydroxylase immunostaining patterns. After administration of either the D1 antagonist SCH 23390 (0.1 mg/kg s.c.), or injection of EAA receptor agonists-1-glutamate, quisqualate and N-methyl-d-aspartate (all 10 nmol i.c.v.) — and antagonists — amino-phosphono-valeric acid (10 nmol i.c.v.) and dizocilpine (MK801, 0.2 mg/kg i.p.) — no significant differences between the two striata were detected in the voltammetric signals. These results suggest that, in the grafted rats, neurons belonging to the host population, such as the striatal cells bearing D1 receptors or the corticostriatal afferents presumed to contain glutamate, might modulate the DA levels, as was found to occur under normal conditions.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00232434
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  • 22
    Electronic Resource
    Electronic Resource
    Locus coeruleus activation induces perforant path-evoked population spike potentiation in the dentate gyrus of awake rat (1994)
    Springer
    Experimental brain research 102 (1994), S. 165-170 
    Details
    ISSN: 1432-1106
    Keywords: Norepinephrine ; Neuromodulation ; Long-term potentiation ; Cerebellar-hippocampal interaction ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract In vitro norepinephrine (NE) induces both short and long-term β-receptor-mediated potentiation of the perforant path-evoked population spike in the dentate gyrus. NE or locus coeruleus (LC) activation in vivo also produces a β-receptor dependent potentiation of population spike amplitude in anesthetized rat. Studies of behavioral state modulation of population spike amplitude in awake rats, and in rats depleted of NE, however, have led to the hypothesis that LC-NE activation should act to suppress or reduce population spike amplitude in the dentate gyrus of unanesthetized rat. Using glutamate activation of LC in awake unrestrained rats (n=12), the present study provides evidence that LC activation in the awake rat does not reduce, but potentiates, population spike amplitude. The potentiation effect was long-lasting (〉25min) in 50% of the experiments. In addition glutamate ejections in the third lobe of cerebellar rostral vermis produced potentiation of population spike amplitude (n=3) and population excitatory postsynaptic potential slope. Ejections at sites outside the LC and rostral vermis were ineffective (n=5). Behavioral effects of glutamate ejection did not predict the occurrence of potentiation. These data support the hypothesis that phasic activation of LC cells is likely to induce short-term, and possibly long-term, potentiation of dentate gyrus throughput in alert animals.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00232449
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  • 23
    Electronic Resource
    Electronic Resource
    Spontaneous recognition of object configurations in rats: effects of fornix lesions (1994)
    Springer
    Experimental brain research 100 (1994), S. 85-92 
    Details
    ISSN: 1432-1106
    Keywords: Object recognition ; Configural discrimination ; Memory ; Fornix ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The effects of fornix lesions were examined in an object recognition memory test based on spontaneous exploration. In the standard condition an object (A) was presented in the sample phase and then presented again in the test phase alongside a new object (B). Both fornix-transected (Fx) and control (Co) rats spent more time exploring the new object than the familiar object after retention delays of 1 min and 15 min. In two configural conditions designed to test sensitivity to reconfigured stimuli, the original sample (A) was now either re-presented alongside its rearranged version (∀), or the re-arranged version itself (∀) was presented with a new object (B). In the first configural condition, both the Co and Fx rats spent more time exploring the reconfigured sample (∀) than the original version of the sample (A) following a delay of 1 min, but not 15 min. In the second configural condition, both Co and Fx rats spent more time exploring the new object (B) than the reconfigured version of the sample (∀) following a delay of 15 min but not 1 min. These present results do not support Sutherland and Rudy's hypothesis on hippocampal function; however, they demonstrate that memory of objects as well as memory of reconfigured objects could easily be examined in a test based on spontaneous exploratory behaviour.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00227281
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  • 24
    Electronic Resource
    Electronic Resource
    Prolonged responses in rat cerebellar Purkinje cells following activation of the granule cell layer: an intracellular in vitro and in vivo investigation (1994)
    Springer
    Experimental brain research 100 (1994), S. 200-214 
    Details
    ISSN: 1432-1106
    Keywords: Cerebellum ; Plateau ; Facial ; Crus IIa Guinea pig ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract We obtained intracellular recordings of 84 Purkinje cells in vitro from guinea pig slices and of 35 cells in vivo from ketamine-anesthetized rats in order to assess detailed properties of synaptic responses in Purkinje cells following granule cell activation. In vitro, electrical stimulation of the granule cell layer underlying recorded Purkinje cells was used in sagittal slices to predominantly activate synapses on ascending granule cell axons. In vivo, stimulation of the upper lip was used to activate Purkinje cells overlying the upper lip patch in the granule cell layer of crus IIa. In the presence of a GABAA antagonist, Purkinje cells at resting membrane potential responded to both electrical stimulation in vitro and peripheral stimulation in vivo, with a depolarization of 1–10 mV amplitude that lasted for 100–300 ms in the absence of climbing fiber input. Similar prolonged depolarizations could also be induced by brief depolarizing current pulses delivered through the recording electrode, demonstrating that either synaptic or direct depolarization may activate inward currents leading to a sustained response. In support of this hypothesis we found that prolonged depolarizations were shortened significantly when stimulation in the granule cell layer or intracellular current pulses were delivered during hyperpolarizing current steps. Stimulation in the granule cell layer or intracellular current pulses delivered during periods of spontaneous somatic spiking resulted in prolonged depolarizations in dendritic recordings, which were accompanied by an increase in somatic spiking frequency. Following upper lip stimulation in vivo, this increase in somatic spiking was interrupted by an inhibition of 10–50 ms duration. In a majority of recordings, this inhibition did not completely abolish prolonged depolarizations, however, and a delayed increase in somatic spike frequency was still observed. These results suggest that prolonged increases in Purkinje cell spike frequency following peripheral stimulation are due to an underlying prolonged dendritic depolarization induced by granule cell input. Further, a single, short burst of input via ascending granule cell axons appears to be sufficient to induce these responses.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00227191
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  • 25
    Electronic Resource
    Electronic Resource
    Subthreshold rectification in neostriatal spiny projection neurons (1994)
    Springer
    Experimental brain research 100 (1994), S. 239-249 
    Details
    ISSN: 1432-1106
    Keywords: Neostriatum ; In vitro brain slices Inward rectification ; Subthreshold ion conductances Firing pattern ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Intracellular recordings from slice preparations were used to assess the subthreshold electrophysiological behavior of rat neostriatal projection neurons. Both current steps and ramp currents were used to estimate the current-voltage relationship (I–V plot). Inward rectification in the subthreshold range was a characteristic of most neurons. The amount of rectification varied greatly, and it was complex: membrane voltage trajectories in response to ramps were made up by almost piecewise changes in the rate of voltage rise, suggesting that multiple conductances contribute to the subthreshold range. Inward current blockers such as tetrodotoxin (TTX) or Cd2+ decreased inward rectification, whereas outward current blockers such as tetraethylammonium (TEA) or 4-aminopyridine (4-AP) increased inward rectification. However, most inward rectification was due to TEA- and Cs+-sensitive conductances and not to TTX- or Cd2+-sensitive conductances. Cs+-sensitive conductances predominated at more negative membrane potentials, whereas 4-AP-sensitive conductances predominated at just ±10 mV below the firing threshold. In spite of a very slow activation, there was evidence for transient outward currents modulating the response, i.e., 4-AP-sensitivity, and voltage-sensitivity for firing frequency and threshold. TEA-sensitive conductances also contributed toward fixing the firing threshold. These results imply the contribution of various ion conductances on the shaping of the characteristic physiological firing recorded in vivo. Modulation of these responses by transmitters or peptides may help to understand neural processing in the neostriatum.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00227194
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  • 26
    Electronic Resource
    Electronic Resource
    Bilateral phasic increases in dorsal root ganglia nerve growth factor synthesis after unilateral sciatic nerve crush (1994)
    Springer
    Experimental brain research 101 (1994), S. 53-58 
    Details
    ISSN: 1432-1106
    Keywords: Nerve growth factor ; NGF mRNA ; Sciatic nerve crush ; Dorsal root ganglia ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The amount of nerve growth factor (NGF) in the L5, L6, and cervical dorsal root ganglia of rats was examined from 1 to 30 days after a unilateral crush lesion of the sciatic nerve and adjacent branches of the lumbar plexus at the level of the sciatic notch. Unilateral nerve crush produced increases in NGF content of lumbar ganglia at 1, 4, and 7–8 days after injury, with increased NGF mRNA at 4 and 7–8 days. Increases in NGF at 1 and 4 days were most pronounced on the unlesioned side while increases at days 7 and 8 were most pronounced on the lesioned side. NGF content increased in cervical ganglia of nerve-lesioned animals at 3 and 7 days after injury and in lumbar and cervical ganglia of sham-operated animals 3–5 days after surgery, with no comparable changes in NGF mRNA. Elevations of ganglionic NGF coincide temporally with some of the alterations in metabolism and morphology which occur in dorsal root ganglion neurons after sciatic nerve crush. However, the bilateral nature of increases in NGF demonstrates that the factor(s) producing the response is not restricted to ganglia axotomized by the injury. The data suggest that ganglionic NGF may be regulated by systemic factors, produced during stress or trauma, as well as by factors from the denervated target tissue and/or regenerating axons.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00243216
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  • 27
    Electronic Resource
    Electronic Resource
    Estrogen reduces the excitability of the female rat medial amygdala afferents from the medial preoptic area but not those from the lateral septum (1994)
    Springer
    Experimental brain research 101 (1994), S. 1-7 
    Details
    ISSN: 1432-1106
    Keywords: Amygdala ; Estrogen ; Preoptic area ; Septum ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Electrical stimulation of the medial amygdala (AMY) elicited antidromic action potentials in neurons in the preoptic area (POA) and the lateral septum (LS) of 36 urethane-anesthetized ovariectomized female rats, which were either treated with estrogen o not treated. The extracellular potentials from the two sites showed similar characteristics, with the exception of the sensitivity to estrogen: they had latencies between 3 and 35 ms. Thresholds were as low as 100 μA. The mean relative refractory period was 2.2 ms. The peak-to-peak amplitudes of the positive-negative biphasic potential ranged from 1.0 mV to 12.0 mV. Estrogen had site-specific effects on parameters of antidromic activation in the POA. Estrogen-treated rats had a significantly higher threshold (937 vs 664 μA) and a longer refractory period (2.5 vs 2.1 ms) than the ovariectomized rats (P 〈 0.05 for each). The effects were absent in the LS. Selective cutting of the stria terminalis diminished the AMY-induced antidromic responses in the POA and LS. Electrical stimulation of the stria blocked the AMY-induced antidromic potentials by collision. Thus, estrogen-sensitive POA efferents as well as non-estrogen-sensitive LS efferents project to the AMY via the stria terminalis. Reductions in axonal excitability would inhibit neural conduction and transmission. Estrogen may therefore reduce the AMY inputs from the POA, without affecting those from the LS. Such alterations in the neural impulse flow may underlie estrogen-dependent neuroendocrine or behavioral regulation.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00243211
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  • 28
    Electronic Resource
    Electronic Resource
    Serotonin reveals ineffective spinal pathways to contralateral phrenic motoneurons in spinally hemisected rats (1994)
    Springer
    Experimental brain research 101 (1994), S. 35-43 
    Details
    ISSN: 1432-1106
    Keywords: Respiratory control ; Phrenic nerve ; Motoneuron ; Spinal hemisection ; Serotonin ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Serotonin reveals ineffective (subthreshold) pathways from the C2 lateral funiculus to ipsilateral phrenic motoneurons in spinalized rats. The objective of the present study was to investigate serotonergic modulation of crossed-spinal pathways to contralateral phrenic motoneurons. Rats (n = 10) were anesthetized (urethane), paralyzed, vagotomized, and artificially ventilated. The spinal cord was hemisected at C1–C2 and, on the intact side, a tungsten stimulating electrode was placed ventral to the C2 dorsal root entry zone in the dorsolateral (∼ 1.1 mm) or the ventrolateral funiculus (∼2.2 mm depth). Single shocks (100–750 μA, 0.1–0.5 ms, 2 Hz) elicited a short-latency (∼ 1.0 ms to peak) excitation in the ipsilateral phrenic nerve, but usually evoked little or no response in the contralateral phrenic nerve at either stimulus site. Following systemic injection of the monoamine oxidase inhibitor pargyline (25 mg/kg) and the serotonin precursor 5-hydroxytryptophan (5–10 mg/kg), complex responses were revealed in the contralateral phrenic nerve, including; (1) spontaneous tonic activity; (2) a short-latency (∼1.0 ms to peak) evoked excitation; and (3) two long-latency (∼2.2 and 7.8 ms to peak) evoked excitations. The longest latency excitation was expressed only when the stimulating electrode was positioned in the dorsolateral funiculus. Contralateral evoked responses were blocked by systemic methysergide (2–6 mg/kg), a broad-spectrum serotonin receptor antagonist. These results indicate that serotonin converts ineffective crossed phrenic pathways in the spinal cord to effective pathways. It remains to be determined whether serotonin is both necessary and sufficient in this modulatory process, or if it is a nonspecific result of increased phrenic motoneuron excitability.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00243214
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  • 29
    Electronic Resource
    Electronic Resource
    Influence of acid-base changes on the intracellular calcium concentration of neurons in primary culture (1994)
    Springer
    Experimental brain research 101 (1994), S. 265-271 
    Details
    ISSN: 1432-1106
    Keywords: Calcium ions ; Neurons ; Acid-base changes ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The influence of changes in intra- and extracellular pH (pHi and pHe, respectively) on the cytosolic, free calcium concentration ([Ca2+]i) of neocortical neurons was studied by microspectrofluorometric techniques and the fluorophore fura-2. When, at constant pHe, pHi was lowered with the NH4Cl prepulse technique, or by a transient increase in CO2 tension, [Ca2+]i invariably increased, the magnitude of the rise being proportional to ΔpHi. Since similar results were obtained in Ca2+-free solutions, the results suggest that the rise in [Ca2+]i was due to calcium release from intracellular stores. The initial alkaline transient during NH4Cl exposure was associated with a rise in [Ca2+]i. However, this rise seemed to reflect influx of Ca2+ from the external solution. Thus, in Ca2+-free solution NH4Cl exposure led to a decrease in [Ca2+]i. This result and others suggest that, at constant pHe, intracellular alkalosis reduces [Ca2+]i, probably by enhancing sequestration of calcium. When cells were exposed to a CO2 transient at reduced pHe, Ca2+ rose initially but then fell, often below basal values. Similar results were obtained when extracellular HCO 3 - concentration was reduced at constant CO2 tension. Unexpectedly, such results were obtained only in Ca2+-containing solutions. In Ca2+-free solutions, acidosis always raised [Ca2+]i. It is suggested that a lowering of pHe stimulates extrusion of Ca2+ by ATP-driven Ca2+/2H+ antiport.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00228746
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  • 30
    Electronic Resource
    Electronic Resource
    Sex differences in GABA/benzodiazepine receptor changes and corticosterone release after acute stress in rats (1994)
    Springer
    Experimental brain research 101 (1994), S. 297-306 
    Details
    ISSN: 1432-1106
    Keywords: GABA receptors ; Benzodiazepine receptors ; Stress ; Corticosterone ; Sex differences ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Since many hormonal indices of stress responsiveness are sexually dimorphic in rats, we examined sex differences and the effects of gonadectomy on the stress-related changes in GABAA/benzodiazepine receptors in rats. Intact or ovariectomized female rats displayed a markedly greater corticosterone response and a more pronounced increase in benzodiazepine receptors than males (intact or orchidectomized) after acute handling or swim stress. Swim stress increased benzodiazepine receptor density without modifying affinity in cortex, hippocampus, and hypothalamus. Corticosterone treatment induced benzodiazepine receptor levels comparable to those seen after swim stress in all hormone groups. Handling stress also enhanced cortical low-affinity GABAA receptor levels in males and ovariectomized females. Both GABA and benzodiazepine receptor levels were positively correlated with circulating corticosterone levels in female, but not male, groups. GABA/benzodiazepine coupling was unaffected by stress or hormonal status. These sexual dimorphisms in hormonal responses to stress may help elucidate the causes and consequences of stress-induced changes in the GABAA/benzodiazepine receptor complex.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00228750
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  • 31
    Electronic Resource
    Electronic Resource
    Platelet-derived growth factor exerts trophic effects on rat striatal DARPP-32-containing neurons in culture (1994)
    Springer
    Experimental brain research 101 (1994), S. 291-296 
    Details
    ISSN: 1432-1106
    Keywords: Platelet-derived growth factor ; Striatal neurons ; DARPP-32 ; Huntington's disease ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The objective of the present study was to determine if either of the two isoforms of platelet-derived growth factor (PDGF), PDGF-AA and PDGF-BB, exerts trophic effects in vitro on developing rat striatal neurons. Striatal neurons were identified using immunocytochemistry for dopamine- and adenosine 3':5'-monophosphate-regulated phosphoprotein with a molecular weight of 32 kilodalton (DARPP-32). In control cultures without PDGF, the mean number of DARPP-32-positive neurons decreased by 47% at days 3 to 5 in vitro. PDGF-BB, but not PDGF-AA, significantly increased the number of DARPP-32-positive neurons both at day 3 (by 42%) and day 5 (by 149%). Total cell number was similar in control and PDGF BB-treated cultures, suggesting that, in striatal cultures, the action of PDGF-BB is relatively specific for DARPP-32-positive neurons. The DARPP-32-positive neurons in PDGF-BB-treated cultures had longer neurites and larger soma areas than those in control and in PDGF-AA-treated cultures. Our data provide evidence that PDGF-BB exerts a trophic action on striatal DARPP-32-positive neurons in vitro by promoting cell survival and morphological differentiation, although a stimulatory effect on intraneuronal DARPP-32 levels also is possible. The findings raise the possibility that PDGF-BB might also be involved in the development and maintenance of striatal neurons in vivo, and could be used to counteract striatal degeneration in models of Huntington's disease.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00228749
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  • 32
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    Synaptic connectivity of serotonin graft efferents in the suprachiasmatic and supraoptic nuclei of the hypothalamus (1994)
    Springer
    Experimental brain research 101 (1994), S. 353-364 
    Details
    ISSN: 1432-1106
    Keywords: Transplantation ; Serotonin neurons ; Hypothalamus ; Electron microscopy ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract We have previously reported that a cell suspension from the rostral part of the embryonic raphe grafted to the basal hypothalamus of 5,7-dihydroxytryptamine-denervated rats produced incomplete serotonin (5-HT) re-innervation of the suprachiasmatic nucleus (SCN) as opposed to hyper-innervation of the supraoptic nucleus (SON). We took advantage of this experimental model to investigate whether the graft-derived, 5-HT fibres retained normal ultrastructural features, and, particularly, a normal density of synaptic junctions, irrespective of the extent of target re-innervation. The intrinsic features of immunostained, graft-derived 5-HT axonal varicosities in both the SCN (ventral portion) and the SON were essentially similar to those exhibited by the respective endogenous innervation. Analysis of well-preserved varicosities in uninterrupted series of thin sections allowed us to evaluate directly the proportions of junctional to non-junctional 5-HT varicosities in both regions. Synaptic incidences were also remarkably conserved after grafting (45.5% in the SCN versus 38.5% in the SON; 48% and 38% in normal rats, respectively). Synapses were primarily reestablished on dendritic shafts, which also were identified as the major post-synaptic targets of the normal 5-HT innervations. We noted, however, a tendency toward increased numbers of symmetrical versus asymmetrical synapses in both the SCN and SON of grafted rats. Thus, irrespective of whether hypo-or hyper-innervation patterns developed post-grafting, the transplanted 5-HT neurons essentially retained normal ultrastructural features in their target territories, with a normal incidence of synaptic junctions. The data provide further support to the hypothesis that the innervation territory is the major determinant of the frequency with which ingrowing 5-HT fibres make synaptic junctions.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00227329
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    Electronic Resource
    An interaction between glucose and estrogen in gastric acid secretion in the lateral hypothalamic area of female rats (1994)
    Springer
    Experimental brain research 102 (1994), S. 171-174 
    Details
    ISSN: 1432-1106
    Keywords: Estrogen ; Gastric acid secretion ; Glucose ; Hypothalamus ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Gastric acid outputs caused by glucose injection into the lateral hypothalamic area (LHA) were examined in insulin hypoglycemia with or without estradiol-17β (EST) administration in bilaterally ovariectomized (OV) female rats. The basal level of acid output was higher in OV rats without EST than in OV rats with EST. When acid response was expressed as the percentage change, glucose injection into the LHA decreased acid output in a dose-dependent fashion in OV rats, while, in OV rats with EST, glucose injection into the LHA also reduced acid output without dose dependency. It was also noted that the threshold concentration of glucose that induced an acid response was lower in OV rats without EST than in OV rats with EST. These findings suggest that glucose-sensitive neurons responsible for gastric acid secretion can be modulated by estrogen at the LHA level.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00232450
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  • 34
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    Ibotenic acid lesions of the striatum reduce drug-induced rotation in the 6-hydroxydopamine-lesioned rat (1994)
    Springer
    Experimental brain research 101 (1994), S. 365-374 
    Details
    ISSN: 1432-1106
    Keywords: 6-Hydroxydopamine ; Ibotenic acid ; Rotation ; Amphetamine ; Apomorphine ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Lesions of the dopaminergic nigrostriatal tract produce a range of motor and sensorimotor deficits. One of the simplest and most reliable is the rotational response of the animal following activation with drugs that stimulate the dopaminergic network, most notably amphetamine and apomorphine. Consequently, the rotation test has been extensively used in assessing the success of treatments designed to restore dopaminergic function, including neural transplants. The present study investigates whether rotation induced by 6-hydroxydopamine lesions of the nigrostriatal bundle in rats is modified by additional lesions in the neostriatum. It was found that apomorphine-induced rotation can be reduced by ibotenic acid lesions of the dopamine-deafferented striatum, and that the extent of the reduction was proportional to the size of the lesions. In contrast, such lesions produced a non-significant reduction in amphetamine-induced rotation, although the correlation between the extent of the reduction and the size of the lesion was again apparent. Since the pattern of change was similar in direction, albeit smaller in magnitude, than the previously reported effects of intrastriatal transplantation in rats with similar nigrostriatal lesions, rotation tests alone do not provide an unequivocal test of graft survival and function.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00227330
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  • 35
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    Monosynaptic innervation of facial motoneurones by neurones of the parvicellular reticular formation (1994)
    Springer
    Experimental brain research 101 (1994), S. 427-438 
    Details
    ISSN: 1432-1106
    Keywords: Facial motor nucleus ; Reticular formation ; Biocytin ; Cholera toxin B ; Synapses ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract In order to determine whether neurones in the parvicellular reticular formation are in direct synaptic contact with motoneurones innervating facial muscles, a combined retrograde and anterograde transport study was carried out in the rat. Animals received injections of the retrograde tracer cholera toxin B conjugated to horseradish peroxidase into facial muscles and of the anterograde tracer biocytin into the parvicellular reticular formation. The facial motor nucleus was then examined for anterograde and retrograde labelling in the light and electron microscopes. Retrogradely labelled neurones were found in the facial motor nucleus with a distribution that was dependent on the muscles injected. Terminals anterogradely labelled with biocytin from the parvicellular reticular formation were observed in the motor nucleus amongst the retrogradely labelled neurones. At the electron microscope, the retrogradely labelled cells were found to receive input from unlabelled terminals and from terminals that were anterogradely labelled from the injections of biocytin in the parvicellular reticular formation. The labelled terminals were 1–2 μm in diameter at the active zone and packed with spherical vesicles. They formed both symmetrical and asymmetrical synapses with their labelled or unlabelled targets. It is concluded that neurones in the parvicellular reticular formation form direct synaptic contact with motoneurones of facial muslces. This may represent a pathway by which the basal ganglia can directly influence orofacial movement, as the substantia nigra is known to project to that part of the reticular formation.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00227336
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  • 36
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    Electronic Resource
    Physiologic effects of nucleus basalis magnocellularis stimulation on rat barrel cortex neurons (1994)
    Springer
    Experimental brain research 102 (1994), S. 21-33 
    Details
    ISSN: 1432-1106
    Keywords: Somatosensory ; Acetylcholine ; Alzheimer's disease ; Nucleus basalis magnocellularis ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Cholinergic neurons in the nucleus basalis magnocellularis (NBM) project to the cerebral cortex and are thought to play an important role in learning and memory, and other cognitive functions. In the present study, we examined the effects of NBM stimulation on the response properties of individual cortical neurons in layer V of the rat somatosensory cortex. Seventy-three neurons were studied before and after a brief electrical stimulation of NBM. Transient changes in spontaneous activity were observed in 60% of the cells, and in most cases this background activity decreased. Recordings lasting more than 1 h stimulation were obtained from 56 cells. Because some NBM stimulation-induced effects lasted several hours, neurons were evaluated in two groups, NBM1 and NBM2. NBM1 neurons were those exposed to either the first NBM stimulation of the day or an NBM restimulation following a more than 5 h stimulation-free period. Neurons exposed to NBM restimulation following a stimulation free interval of less than 5 h were classified as NBM2. Sixty-nine percent of the 32 NBM1 neurons displayed marked decreases in spontaneous activity and/or increases in the response evoked by deflecting a contralateral facial vibrissa. NBM1 stimulation caused some units to respond to previously minimally effective whisker stimuli. Stimulation effects often lasted several hours. By contrast, long-lasting changes were observed in only 25% of the 24 NBM2 neurons, and the only consistent effect was on spontaneous, not stimulus-evoked, activity. Systemic injection of atropine blocked NBM stimulation-induced changes in spontaneous and stimulus-evoked activities. Control neurons, studied without NBM stimulation, failed to display consistent alterations in their response properties during the course of 1 h or more. Results demonstrate that NBM activation produces long-lasting, cholinergically mediated alterations in the response properties of somatosensory cortical neurons. Effects were complex, being influenced by factors such as the time interval between successive stimulations during an experiment. The complexity of these NBM mediated effects should be considered when designing therapies for neurodegenerative disorders characterized by loss of NBM neurons.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00232435
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  • 37
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    Threshold-spacing in motoneurone pools of rat and cat: possible relevance for manner of force gradation (1994)
    Springer
    Experimental brain research 102 (1994), S. 69-74 
    Details
    ISSN: 1432-1106
    Keywords: Motoneurone ; Recruitment ; Force modulation ; Rat ; Cat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract In the context of an analysis concerning factors of importance for the relative contributions of recruitment and rate gradation of muscle force, the distribution of electrical excitability was analyzed for medial gastrocnemius (MG) motoneurones of rat and cat. The experimental data came from previously collected intracellular measurements in animals anaesthetized with pentobarbitone. Electrical excitability was measured as the threshold (nanoamperes) for single spike generation (rheobase) in rat and for maintained repetitive firing (rhythmic threshold) in cat. Furthermore, the data included measurements of axonal conduction velocity and of contractile properties of the muscle units innervated by the studied motoneurones. The units were categorized into types S (slow-twitch, fatigue-resistant), FR (fast-twitch, fatigue-resistant) and FF (fast-twitch, fatiguable) on the basis of the combined criteria of twitch-speed and sensitivity to fatigue. We confirmed that, in spite of the presence of normal-looking symmetrical distributions of axonal conduction velocity, there was a positive skew in the distribution of electrical excitability (relatively high numbers of cells with low thresholds, few with high ones). Within each unit category (S, FR, FF), we ranked the motoneurones according to their relative electrical excitability and calculated the threshold difference between consecutive cells (“threshold spacing”). In accordance with the skewed distribution of electrical excitability, we found that the mean threshold spacing was ranked in the same way as the mean thresholds, i.e. S〈FR〈FF; the statistical analysis showed that, for cats as well as rats, small threshold-spacing steps were significantly more common for S than for FF motoneurones. In the discussion it is pointed out that the narrow threshold-spacing for S units, as compared to FF units, would tend to decrease the relative amount of recruitment-parallel rate modulation in these cells. Thus, the spacing of recruitment thresholds tends to allow the easily recruited S motoneurones to remain firing at relatively low rates during ongoing recruitment gradation, which would be of potential value in promoting a high degree of endurance for long-lasting postural contractions.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00232439
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  • 38
    Electronic Resource
    Electronic Resource
    Rat posterior parietal cortex: topography of corticocortical and thalamic connections (1994)
    Springer
    Experimental brain research 100 (1994), S. 67-84 
    Details
    ISSN: 1432-1106
    Keywords: Cerebral cortex ; Anatomy ; Connections Corticocortical ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Anatomical and functional findings support the contention that there is a distinct posterior parietal cortical area (PPC) in the rat, situated between the rostrally adjacent hindlimb sensorimotor area and the caudally adjacent secondary visual areas. The PPC is distinguished from these areas by receiving thalamic afferents from the lateral dorsal (LD), lateral posterior (LP), and posterior (Po) nuclei, in the absence of input from the ventrobasal complex (VB) or dorsal lateral geniculate (DLG) nuclei. Behavioral studies have demonstrated that PPC is involved in spatial orientation and directed attention. In the present study we used fluorescent retrograde axonal tracers primarily to investigate the cortical connections of PPC, in order to determine the organization of the circuitry by which PPC is likely to participate in these functions, and also to determine how the topography of its thalamic connections differs from that of neighboring cortical areas. The cortical connections of PPC involve the ventrolateral (VLO) and medial (MO) orbital areas, medial agranular cortex (area Fr2), portions of somatic sensory areas Par1 and Par2, secondary visual areas Oc2M and Oc2L, auditory area Tel, and retrosplenial cortex. The secondary visual areas Oc2L and Oc2M have cortical connections which are similar to those of PPC, but are restricted within orbital cortex to area VLO, and within area Fr2 to its caudal portion, and do not involve auditory area Te1. The cortical connections of hindlimb cortex are largely restricted to somatic sensory and motor areas. Retrosplenial cortex, which is medially adjacent to PPC, has cortical connections that are prominent with visual cortex, do not involve somatic sensory or auditory cortex, and include the presubiculum. We conclude that PPC is distinguished by its pattern of cortical connections with the somatic sensory, auditory and visual areas, and with areas Fr2, and VLO/MO, in addition to its exclusive thalamic connectivity with LD, LP and Po. Because recent behavioral studies indicate that PPC, Fr2 and VLO are involved in directed attention and spatial learning, we suggest that the interconnections among these three cortical areas represent a major component of the circuitry for these functions in rats.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00227280
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  • 39
    Electronic Resource
    Electronic Resource
    Sensorimotor transformation in a spinal motor system (1994)
    Springer
    Experimental brain research 100 (1994), S. 170-174 
    Details
    ISSN: 1432-1106
    Keywords: Withdrawal reflexes ; Motion analysis Nociception ; Pain ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract To use sensory information from the skin to guide motor behaviour the central nervous system must transform sensory coordinates into movement coordinates. As yet, the basic principles of this crucial neural computation are unclear. One motor system suitable as a model for the study of such transformations is the spinal withdrawal reflex system. The spatial organization of the cutaneous input to these reflexes has been characterized, and we now introduce a novel method of motion analysis permitting a quantitative analysis of the spatial input-output relationship in this motor system. For each muscle studied, a “mirror-image” relationship was found between the spatial distribution of reflex gain for cutaneous input and the pattern of cutaneous unloading ensuing on contraction. Thus, there is an “imprint” of the movement pattern on this motor system permitting effective sensorimotor transformation. This imprint may indicate the presence of a learning process which utilizes the sensory feedback ensuing on muscle contraction.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00227291
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  • 40
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    Electronic Resource
    Expression of major histocompatibility complex class II antigen on amoeboid microglial cells in early postnatal rat brain following intraperitoneal injections of lipopolysaccharide (1994)
    Springer
    Experimental brain research 100 (1994), S. 287-292 
    Details
    ISSN: 1432-1106
    Keywords: Amoeboid microglia Major histocompatibility complex Type 3 complement receptor ; Endotoxin ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract In rats given two single intraperitoneal injections of lipopolysaccharide (LPS) at 1 and 4 days of age and killed at 7 days of age, 11.5–12% of amoeboid microglial cells (AMC) in the supraventricular corpus callosum were induced to express major histocompatibility complex (MHC) class II antigen, as detected with monoclonal antibody OX-6. The MHC class II antigen induced was colocalized with MHC class I antigen and type 3 complement receptors on the same cells. The expression of MHC class II antigen on the plasma membrane of AMC was confirmed in immunoelectron microscopy. Although OX-6-positive AMC often assumed a perivascular position, the majority of them, however, were far removed from the blood vessels. The cytoplasmic processes of the perivascular OX-6-positive AMC appeared to rest directly on the vascular lamina, and in some section profiles they were in contact with a large surface area of the outer wall of small blood vessels. It is concluded from this study that although MHC class II antigen is not constitutively present on AMC, it is, however, inducible under stimulation with LPS. It is, therefore, suggested that the OX-6-positive AMC, especially the perivascular AMC, may have the potentiality to function as antigen-presenting cells in the developing brain when challenged by LPS.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00227198
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  • 41
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    Lowering of extracellular pH suppresses low-Mg2+-induces seizures in combined entorhinal cortex-hippocampal slices (1994)
    Springer
    Experimental brain research 101 (1994), S. 44-52 
    Details
    ISSN: 1432-1106
    Keywords: Acidosis ; Seizures ; Brain slices ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Lowering [Mg2+]o induces epileptiform bursting in hippocampus and entorhinal cortex (EC), presumably by activation of N-methyl-d-aspartate (NMDA) receptors. Since increasing [H+]o has been shown to reduce NMDA receptor activation, we hypothesized that this could contribute to anticonvulsant actions of acidic pH. To test this, we studied the effects of raising extracellular PCO2 (20.6%, pH = 6.7) or lowering extracellular pH (6.7 or 6.2) on low-Mg2+-induced epileptiform discharges. Lowering the pH to 6.7 by either means increased the interval between seizure-like events (SLEs), decreased the maximal amplitude of SLEs, and, if the site of seizure generation was at a distance from the recording site, acidification slowed the rate of seizure propagation. In contrast, the duration of SLEs was unaffected by acidic pH or high PCO2. Raising PCO2 or lowering pH to 6.7 also blocked early (8–10 min) but not late (〉 20 min) phases of status-like discharges. All effects of the extracellular pH changes were fully reversible. Further lowering of extracellular pH to 6.2 completely and reversibly blocked both SLEs and status-like discharges. Our data show that the effects of high PCO2 and low pH on seizures in the EC in vitro may be dose-dependent and consistent with induction by proton blockade of NMDA receptors. Thus, blockade of NMDA currents by protons may be an important component of the anticonvulsant action of extracellular acidosis. The results also suggest that acidosis may be a desirable property for new antiepileptic treatments.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00243215
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  • 42
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    Electronic Resource
    Phosphinic acid derivatives as baclofen agonists and antagonists in the mammalian spinal cord: an in vivo study (1994)
    Springer
    Experimental brain research 101 (1994), S. 59-72 
    Details
    ISSN: 1432-1106
    Keywords: Spinal cord ; Synaptic transmission ; GABAB receptors ; Baclofen agonists and antagonists ; Rat ; Cat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The actions of a series of derivatives of 3-aminopropyl-phosphinic acid as baclofen agonists and antagonists have been examined on the synaptic excitation of neurones by impulses in primary afferent fibres in the lumbar spinal cords of pentobarbitone-anaesthetised cats and rats. Both the pre-and postsynaptic inhibitory actions of microelectrophoretic (-)-baclofen were reduced by similarly administered CGP 35 348, 36 742, 46 381, 52 432, 54 626 and 55 845, the latter being the most potent antagonist. None of these antagonists either decreased or increased the excitability of spinal neurones, and the inhibitory action of GABA was reduced only by local concentrations of antagonists which also reduced the action of piperidine-4-sulphonic acid, a GABAA agonist. Although the weak inhibitory effect of 3-aminopropylphosphinic acid in both the rat and the cat was not reduced by these baclofen antagonists, the pre-and postsynaptic inhibitory effects of 3-aminopropyl-methyl-osphinic acid (CGP 35 024), which was more potent than (-)-baclofen, were reduced by the antagonists. Like (-)-baclofen, CGP 35 024 was relatively ineffective in reducing transmitter release in the cord from the terminals of excitatory spinal interneurones, the terminals of excitatory tracts in the dorsolateral funiculus and the cholinergic terminals of motor axon collaterals. In both rat and cat cords, receptors for (-)-baclofen could not be demonstrated to be activated by microelectrophoretic GABA, possibly because of the predominantly dendritic location of GABAB receptors. Spinal pre-and postsynaptic baclofen receptors appeared to be pharmacologically similar but differed from those in the higher central nervous system of the rat, where 3-aminopropylphosphinic acid has been reported to be an effective baclofen agonist. The compounds tested, particularly CGP 55 845 and 46 381, will be of use in further investigations of the physiological relevance of baclofen receptors at central synapses where GABA may be the transmitter.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00243217
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  • 43
    Electronic Resource
    Electronic Resource
    Re-initiated growth from mature ventral mesencephalon: an in oculo transplant study of nigrostriatal co-grafts (1994)
    Springer
    Experimental brain research 101 (1994), S. 73-85 
    Details
    ISSN: 1432-1106
    Keywords: Substantia nigra ; Striatum ; Transplant Dopamine ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The ability of mature dopaminergic neurons derived from ventral mesencephalon to re-initiate growth after making contact with a non-innervated target was studied using the intra-ocular grafting model. Foetal ventral mesencephalic tissue or brain stem including the locus coeruleus area was grafted to the anterior chamber of the eye. Two weeks, 6 weeks or 1 year after the first implantation, foetal striatal tissue was placed in contact with the nigral graft or grafted alone. The size of the transplants was measured through the cornea. The final size of the striatal grafts was significantly larger when placed alone than when co-grafted with 1-year-old or 6-week-old dopaminergic grafts. Striatum grafted together with 2-week-old nigra was larger than when grafted adjacent to mature substantia nigra, but not significantly so. Nerve fibre outgrowth into the iris from the nigral transplants did not increase after maturation, but the re-innervated area of the host iris progressively increased around the locus coeruleus grafts. Ingrowth of tyrosine hydroxylase (TH) immunoreactive nerve fibres into the striatal grafts was studied 6 weeks after the second implantation. TH immunohistochemistry revealed innervation of the striatal piece in all cases, except for the group where striatum alone was grafted. With the short survival time for cografts of 6 weeks, TH-positive nerve fibres innervated a larger volume, had a patchy appearance and the density was higher in striatum grafted to 2 week-old nigral transplants than that seen in striatal transplants grafted to mature nigral grafts. The patchy pattern of TH-immunoreactive nerve terminals was also seen in striatum co-grafted with 6-week-old or 1-year-old nigral transplants. No difference in striatal innervation volume was detected between those latter two groups. When striatum was implanted adjacent to mature ventral mesencephalon and grown together for 6 months — the longer survival time — the same dense TH-positive innervation as seen in striatum co-grafted with immature nigral tissue at the shorter survival time was found. Additionally, the nigral part of the co-grafts showed increased TH-immunoreactive nerve fibre density. In conclusion, dopaminergic neurites from mature ventral mesencephalic transplants can re-initiate growth if placed in contact with non-innervated striatal tissue. The nigral grafts do not progressively re-innervate the host iris, while locus coeruleus grafts do. The intra-ocular grafting model can be used to study the in vivo effects of trophic factors on mature dopaminergc neurons.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00243218
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  • 44
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    Projections from the presubiculum and the parasubiculum to morphologically characterized entorhinal-hippocampal projection neurons in the rat (1994)
    Springer
    Experimental brain research 101 (1994), S. 93-108 
    Details
    ISSN: 1432-1106
    Keywords: Hippocampal formation ; Parahippocampal cortex ; Perforant pathway ; Limbic system ; Neuroanatomy ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The relations between the inputs from the presubiculum and the parasubiculum and the cells in the entorhinal cortex that give rise to the perforant pathway have been studied in the rat at the light microscopical level. Projections from the presubiculum and the parasubiculum were labeled anterogradely, and, in the same animal, cells in the entorhinal cortex that project to the hippocampal formation were labeled by retrograde tracing and subsequent intracellular filling with Lucifer Yellow. The distribution and the number of appositions between the afferent fibers and hippocampal projection neurons in the various layers of the entorhinal cortex were analyzed. The results show that layers I–IV of the entorhinal cortex contain neurons that give rise to projections to the hippocampal formation. The morphology of these projection neurons is highly variable and afferents from the presubiculum and the parasubiculum do not show a preference for any specific morphological cell type. Both inputs preferentially innervate the dendrites of their target cells. However, presubicular and parasubicular projections differ with respect to the layer of entorhinal cortex they project to. The number of appositions of presubicular afferents with cells that have their cell bodies in layer III of the entorhinal cortex is 2–3 times higher than with cells in layer II. In contrast, afferents from the parasubiculum form at least 2–3 times as many synapses on the dendrites of cells located in layer II than on neurons that have their cell bodies in layer III. Cells in layers I and IV of the entorhinal cortex receive weak inputs from the presubiculum and parasubiculum. Not only is the presubiculum different from the parasubiculum with respect to the distribution of projections to the entorhinal cortex, they also differ in their afferent and efferent connections. In turn, cells in layer II of the entorhinal cortex differ in their electrophysiological characteristics from those in layer III. Moreover, layer II neurons give rise to the projections to the dentate gyrus and field CA3/CA2 of the hippocampus proper, and cells in layer III project to field CA1 and the subiculum. Therefore, we propose that the interactions of the entorhinal-hippocampal network with the presubiculum are different from those with the parasubiculum.
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    URL: http://dx.doi.org/10.1007/BF00243220
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  • 45
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    Electronic Resource
    Pharmacokinetics of factor IX in patients with haemophilia B (1994)
    Springer
    European journal of clinical pharmacology 46 (1994), S. 325-332 
    Details
    ISSN: 1432-1041
    Keywords: Factor IX ; Haemophilia B ; macromolecules ; pharmacokinetics ; methodological study
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract The aims of this study were to investigate the influence of total blood sampling time on the estimated pharmacokinetic parameters of Factor IX procoagulant activity (FIX:C) and to relate the pharmacokinetics of FIX:C to the putative physiological disposition of Factor IX (FIX). Six patients with severe haemophilia B each received 2 infusions of FIX and on both occasions blood samples were collected for 104 h. Each FIX:C decay curve was processed with successive deletion of the last (remaining) datapoint. The fitted terminal half-life (t1/2β) and the calculated model-independent mean residence time (MRTMI), elimination clearance (CLMI) and volume of distribution at steady state (Vss) stabilised close to their final values when FIX:C data corresponding to at least 56 h of sampling were used. The final mean values were t1/2β=34 h, MRTMI=37 h, CLMI=4.0 ml · h-1 · kg-1 and Vss=0.15 l · kg-1. The disposition of FIX could be characterised by a two-compartment pharmacokinetic model. On average, FIX molecules spent 44% of their total MRT in the second (or “extravascular”) compartment. The distribution clearance was comparable to estimated total lymph flow. The volume of the central compartment was twice the estimated plasma volume, which may reflect the rapid and reversible binding of FIX to vascular endothelium. This explains the common clinical finding that the peak activity of FIX:C is less than the injected dose divided by the estimated plasma volume of the patient.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00194400
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  • 46
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    Electronic Resource
    Dose proportionality of iopromide pharmacokinetics and tolerability after IV injection in healthy volunteers (1994)
    Springer
    European journal of clinical pharmacology 46 (1994), S. 339-343 
    Details
    ISSN: 1432-1041
    Keywords: Iopromide ; X-ray contrast medium ; pharmacokinetics ; tolerability ; healthy volunteers ; adverse effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Twelve healthy male volunteers participated in a single-blind, randomised, placebo-controlled cross-over study of IV iopromide in doses of 15 g iodine or 80 g iodine infused over a period of 15 min. The volunteers were observed for three days during which time blood samples, urine and faeces were collected. The terminal disposition phase half-life of iopromide was 2 h and 1.9 h, and the total clearance was 110 and 103 ml·min-1 at the lower and at the higher dose levels, respectively. The steady state volume of distribution was 16 and 17 l, indicating predominantly extracellular distribution of iopromide. Statistical analysis (one-sided t-test) showed that all the target parameters (AUC, half-life and urinary excretion) were equivalent at both dose levels, indicating dose proportionate, first order kinetics of iopromide over the large dose range tested. Iopromide was well tolerated after both doses.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00194402
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  • 47
    Electronic Resource
    Electronic Resource
    The pharmacokinetics of recombinant human erythropoietin after subcutaneous injection at different sites (1994)
    Springer
    European journal of clinical pharmacology 46 (1994), S. 333-337 
    Details
    ISSN: 1432-1041
    Keywords: Erythropoietin ; recombinant human erthropoietin ; pharmacokinetics ; subcutaneous ; absorption ; bioavailability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract The pharmacokinetics of recombinant human erythropoietin (RhEPO) were investigated after subcutaneous (s.c.) injection in the thigh and in the abdominal wall. Eleven healthy subjects, age 24.4 years (median), were studied. Each subject received two s.c. injections of 100 U·kg-1 RhEPO dissolved in 1 ml water: one injection in the thigh and another in the abdomen. Serum erythropoietin was measured regularly by radioimmunoassay until 144 h after each injection. The mean residence time was significantly longer after injection in the thigh than in the abdomen (32.7 vs 26.2 h). The estimated half-life of absorption was significantly longer after injection in the thigh than after abdominal application (14.9 vs 12.3 h). The estimated half-life of elimination was not significantly different (4.4 vs 4.8 h). The relative difference in the area under the curve between injection in the abdomen and the thigh in the same subject ranged from -36% to +68% but there was no significant difference in bioavailability. The peak concentration was not significantly different and appeared at around 10 h (Cmax thigh, 175 U·l-1 vs Cmax abdomen, 216 U·l-1). A twin-peak configuration of the concentration vs time curve with a significant second peak at 24 h was found after injection in the thigh but not after abdominal injection. In conclusion, the mean residence time was longer after administration in the thigh, probably due to delayed absorption, but bioavailability was not significantly different. Following injection in the thigh the concentration curve had two peaks. The differences may be due to regional variations in lymph flow and to physical activity. The overall differences in pharmacokinetics appeared to be too small to recommend a general preference of the injection site.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00194401
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  • 48
    Electronic Resource
    Electronic Resource
    Pharmacokinetics and pharmacodynamics of transdermal dexmedetomidine (1994)
    Springer
    European journal of clinical pharmacology 46 (1994), S. 345-349 
    Details
    ISSN: 1432-1041
    Keywords: Dexmedetomidine ; transdermal ; pharmacokinetics ; α2-adrenoceptor agonist
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Dexmedetomidine is a novel α2-adrenoceptor agonist that may provide beneficial effects as premedication for anesthesia. The pharmacokinetics and pharmacodynamics of transdermal (TD) and intravenous (IV) dexmedetomidine were studied in nine healthy male subjects in a crossover trial. The TD preparation, containing 625 μg of dexmedetomidine base, was applied on the forehead and left in place for 12 h. The IV dose (2.0 μg·kg-1 as dexmedetomidine hydrochloride) was administered as an infusion over 5 min. Dose-normalized total AUC values were used to calculate dexmedetomidine bioavailability. The bioavailability of dexmedetomidine from the TD preparation was 51%. However, the bioavailability of dexmedetomidine released from the preparation was 88%. The mean terminal half-life was 3.1 h after IV and 5.6 h after TD administration. After TD administration, the mean maximal reductions in blood pressure (systolic/diastolic) and heart rate were 28/20 mmHg and 19 beats·min-1. A sedative effect was obvious within 5 min and 1–2 h after IV and TD administration, respectively.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00194403
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  • 49
    Electronic Resource
    Electronic Resource
    Pharmacokinetics and absolute bioavailability of colchicine after i. v. and oral administration in healthy human volunteers and elderly subjects (1994)
    Springer
    European journal of clinical pharmacology 46 (1994), S. 351-354 
    Details
    ISSN: 1432-1041
    Keywords: Colchicine ; pharmacokinetics ; healthy volunteers ; elderly subjects ; absolute bioavailability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract The pharmacokinetics of colchicine were studied in six healthy male and four elderly female volunteers after i. v. and oral administration. Plasma samples were collected over 72 h and assayed for colchicine by a specific and sensitive radioimmunoassay. Plasma concentration-time curves were fitted using a three-compartmental model after i. v. administration of 0.5 mg (healthy volunteers) and 1 mg (elderly group) colchicine. The first distribution half-life (t1/2 λ1) was short: 9.2 min in healthy volunteers and 3.0 min in the elderly group; the second distribution half-life (t1/2 λ2) was of the same order for both groups, 1.2 h. Plasma elimination half-lives were also in the same range: 30 h for healthy volunteers versus 34 h for the elderly subjects. Mean residence time was also in the same range in the two groups: 27 h in healthy volunteers and 21 h for elderly subjects. The volume of distribution (Vz) was 6.71·kg-1 for the healthy group and 6.31·kg-1 for the elderly group, while Vss was smaller: 4.21·kg-1 for healthy volunteers and 2.91·kg-1 for elderly subjects. Total body clearance was 10.51·h-1 for healthy and 5.51·h-1 for elderly subjects. After oral administration of 1 mg, lag-time was 14 min in healthy volunteers and 11 min in elderly subjects. Maximal plasma concentration was 5.5 ng·ml-1 at 62 min in the healthy group, while in the elderly group Cmax was 12 ng·ml-1 at 87 min. Mean absolute bioavailability of the tablet was the same in both groups, 44% for healthy volunteers and 45% for elderly subjects.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00194404
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  • 50
    Electronic Resource
    Electronic Resource
    Availability of synthetic salmon calcitonin in tissue fluid after a single intravenous dose (1994)
    Springer
    European journal of clinical pharmacology 46 (1994), S. 371-373 
    Details
    ISSN: 1432-1041
    Keywords: Salmon calcitonin ; Skin blister fluid concentration ; synthetic ; plasma concentration ; pharmacokinetics ; adverse effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract To obtain further information about the availability of salmon calcitonin in the biophase compartment that surrounds the receptor site, salmon calcitonin concentrations in plasma and skin blister fluid (SBF) after a single IV dose of 100 IU synthetic salmon calcitonin were compared in 15 healthy volunteers. Serial blood and SBF samples were collected before and up to 8 h after administration and calcitonin was determined by a specific RIA. The maximum concentration in plasma was 225 pg·ml-1 (in the first sample at 15 min), whereas in SBF the mean peak of 84 pg·ml-1 was reached after about 30 min. The distribution of salmon calcitonin into SBF, defined as the ratio of the AUCs in SBF and plasma, was 1.5. The kinetic profiles of salmon calcitonin in plasma and interstitial fluid were different. Calcitonin in plasma peaked and then levelled out, while in SBF it persisted longer than in plasma. This is the first report of the distribution of salmon calcitonin into blister fluid.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00194408
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  • 51
    Electronic Resource
    Electronic Resource
    Food-induced increase in bioavailability of 5-methoxypsoralen (1994)
    Springer
    European journal of clinical pharmacology 46 (1994), S. 375-377 
    Details
    ISSN: 1432-1041
    Keywords: 5-Methoxypsoralen ; Psoriasis ; food ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract 5-Methoxypsoralen (5-MOP) in combination with ultraviolet light exposure is used for the treatment of psoriasis. The effect of food on the pharmacokinetics of 5-MOP was evaluated in a randomized, crossover study in nine healthy subjects. Each subject received the tablets with a standardized breakfast or under fasting conditions. The food had a dramatic effect on the bioavailability of 5-MOP. Five of the subjects showed no measurable quantities (detection limit of the analytical technique 1 ng·ml-1) of 5-MOP when the drug was given under fasting conditions. However, plasma peak concentration within the range 37–144 ng·ml-1 (median 102 ng·ml-1) was measured when the drug was taken with food. The time for the plasma peak concentration was within the range 2.0–5.1 h (median 3.0 h) under non-fasting conditions. The elimination half-life was within the range 1.4–2.7 h (median 1.9 h). We conclude that it is imperative that 5-MOP tablets are administered together with food.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00194409
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  • 52
    Electronic Resource
    Electronic Resource
    Pharmacokinetics of ganciclovir in a patient undergoing chronic haemodialysis (1994)
    Springer
    European journal of clinical pharmacology 46 (1994), S. 379-381 
    Details
    ISSN: 1432-1041
    Keywords: Ganciclovir ; Renal failure ; pharmacokinetics ; haemodialysis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract The pharmacokinetics of ganciclovir was evaluated in a 73-year old anuric, haemodialyzed patient given 1.25 mg·kg-1 at the end of each haemodialysis session, three times per week. A biexponential decrease in plasma ganciclovir was observed, with a peak concentration of 3.7 mg·1-1 followed by a steady state value of 2.6 mg·1-1 for almost 40 h. The total plasma clearance was 0.05 ml·min-1·kg-1, the volume of distribution at steady state was 0.61·kg-1, the elimination half life was 132 h, the area under curve was 372 μg·h·ml-1, the mean residence time was 190 h, and the percentage of ganciclovir cleared from plasma after a 5 h haemodialysis session was 52.1%. The simulated pharmacokinetics over one month, following the same scheme of administration, did not suggest marked accumulation of ganciclovir. These results were obtained after a reduction of 58% in the recommended dose in patients with impaired renal function.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00194410
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  • 53
    Electronic Resource
    Electronic Resource
    Esmolol, an ultrashort-acting, selective β1-adrenoceptor antagonist: pharmacodynamic and pharmacokinetic properties (1994)
    Springer
    European journal of clinical pharmacology 46 (1994), S. 399-404 
    Details
    ISSN: 1432-1041
    Keywords: Esmolol ; β1-Adrenoceptor antagonist ; tricresylphosphate ; pharmacokinetics ; effect kinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract The effects of esmolol at different rates of infusion (100, 250 and 500 μg·kg−1 BW·min−1) were compared with β-adrenoceptor occupancy (β1 and β2, estimated by a subtype selective radioreceptor assay) and plasma concentrations of esmolol and its acid metabolite were measured by HPLC. Up to a rate of infusion of esmolol of 500 μg·kg−1 BW·min−1 there was a maximal β1-receptor occupancy of 84.7% while β2-receptor occupancy was below the detection limit; confirming the β1 selectivity of esmolol. Exercise-induced increases in heart rate and systolic blood pressure were reduced by esmolol in a dose-dependent manner. The estimated EC50 values of rate of infusion for the reduction in heart rate and systolic blood pressure during exercise were 113 and 134 μg·kg−1 BW · min−1, respectively. Additionally, heart rate and systolic blood pressure were reduced moderately at rest. Because of the short elimination half-life of esmolol caused by the rapid hydrolysis to its acid metabolite, 45 min after end of infusion high plasma concentrations of the metabolite (maximally 80 μg·ml−1) but no esmolol were detectable. Since no in vivo effects have been observed, despite the presence of high plasma concentrations of the metabolite, the metabolite did not participate in the observed effects up to an infusion rate of esmolol of 500 μg·kg−1 BW·min−1. The plasma concentrations of antagonist detected by radioreceptor assay and plasma concentrations of esmolol detected by HPLC showed a good correlation (r=0.97). Since the cardiovascular effects, determined before and 45 min after termination of infusion of esmolol were similar, it can be concluded that the observed effects on heart rate and systolic blood pressure are exclusively mediated by esmolol.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00191900
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  • 54
    Electronic Resource
    Electronic Resource
    On the relation between standard deviation and arithmetic mean in pharmacokinetic studies (1994)
    Springer
    European journal of clinical pharmacology 46 (1994), S. 573-574 
    Details
    ISSN: 1432-1041
    Keywords: Standard deviation ; Arithmetic mean ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00196120
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  • 55
    Electronic Resource
    Electronic Resource
    Changes in clearance create pharmacokinetic pitfalls as illustrated by studies on tiopronin (1994)
    Springer
    European journal of clinical pharmacology 46 (1994), S. 575-575 
    Details
    ISSN: 1432-1041
    Keywords: Renal clearance ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00196121
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  • 56
    Electronic Resource
    Electronic Resource
    Azithromycin does not alter the effects of oral midazolam on human performance (1994)
    Springer
    European journal of clinical pharmacology 47 (1994), S. 49-52 
    Details
    ISSN: 1432-1041
    Keywords: Azithromycin ; Erythromycin ; Midazolam ; drug interaction ; healthy volunteers ; pharmacokinetics ; drug interaction
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Since macrolide antibiotics inhibit the oxidative hepatic metabolism of various drugs, including midazolam, the present double blind studies were conducted to find out if azithromycin, a new macrolide of the azalide type, would inhibit the metabolism of midazolam and enhance the effects of midazolam on human performance. In Study I, 64 healthy medical students, divided in four parallel groups received placebo, midazolam (10 mg or 15 mg), and midazolam 10 mg combined with azithromycin (500mg+250mg). In Study II, three males received oral midazolam 10 mg in combination with placebo, azithromycin or erythromycin 750 mg (as a positive control) in a cross-over trial. Objective and subjective tests were done before the intake of midazolam and 30 and 90 min after it, and venous blood was sampled for the assay of midazolam. In the placebo group in Study I, the mean numbers of letters cancelled (LC) at baseline, 30 min and 90 min were 21, 20 and 20, respectively, and the corresponding mean numbers of correct digit symbol substitutions (DSS) were 126, 137 and 140, indicating a practice effect. Midazolam 10 mg impaired these performances (21, 13 and 12 for LC, and 127, 113 and 111 for DSS). Either dose of midazolam produced clumsiness, mental slowness and poor subjective performance, midazolam 15 mg being slightly more active. The corresponding, scores in the azithromycin + midazolam group were 21, 16, 16 for LC, and 132, 121 and 119 for DSS, the only significant difference from placebo being the impairment of DSS at 90 min. The combination differed from midazolam 15 mg in producing less drowsiness and mental slowness. In Study II, mean plasma midazolam concentrations (μg·1-1) after erythromycin + midazolam 10 mg were 0 (baseline), 168 (30 min) and 113 (90 min), which were higher than the values (0, 79 and 41) after placebo + midazolam. The corresponding concentrations (μg·1-1) after azithromycin + midazolam (0, 85 and 46) were similar to those found after placebo + midazolam. Erythromycin but not azithromycin enhanced the objective and subjective effects of midazolam. Our results suggest that as azithromycin, unlike erythromycin, does not interfere with midazolam metabolism, it also does not enhance the effects of midazolam.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00193477
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  • 57
    Electronic Resource
    Electronic Resource
    Comparative pharmacokinetics of bismuth from ranitidine bismuth citrate (GR122311X), a novel anti-ulcerant and tripotassium dicitrato bismuthate (TDB) (1994)
    Springer
    European journal of clinical pharmacology 47 (1994), S. 177-180 
    Details
    ISSN: 1432-1041
    Keywords: Ranitidine bismuth citrate ; Tripotassium dicitrato bismuthate ; Duodenal ulcer ; bismuth ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract GR122311X (ranitidine bismuth citrate, Glaxo Group Research Ltd.) is a salt of ranitidine with a complex of bismuth and citric acid which is being developed for the treatment of peptic ulceration. In this study, 4 groups of 12 healthy male subjects were dosed for 10 days with either GR122311X 500 mg bid (301 mg bismuth per day), GR122311X 1.0 g bid (602 mg bismuth per day), tripotassium dicitrato bismuthate (TDB, DeNoltab, Gist Brocades Ltd., Weybridge, England) 240 mg bid (431 mg bismuth per day) or placebo. After the last dose the geometric mean for Cmax for 500 mg bid of GR122311X was 5 ng·g−1, for 1.0 g bid GR122311X it was 12 ng·g−1 and it was 21 ng·g−1 for 240 mg TDB bid. The corresponding trough plasma levels were 2 ng·g−1, 4 ng·g−1 and 4 ng·g−1, respectively. The AUC over a dosing interval after the last dose (AUCτ) were 34 ng·h·g−1, 71 ng·h·g−1 and 79 ng·h·g−1, respectively. The bismuth urinary recoveries over the last dosing interval (Aeτ) were 97 μg, 227 μg and 309 μg, respectively, which is less than 1 % of the administered doses. The renal clearance of bismuth was less than the glomerular filtration rate. After adjustment for bismuth dose, the Cmax for GR122311X 500 mg was 35 % that of TDB, while for GR122311X 1.0 g the Cmax was 42 % that of TDB. Similar differences were observed for Aeτ. In conclusion bismuth pharmacokinetics after oral administration of GR1223311X exhibited lower Aeτ and Cmax, with a much narrower Cmax range than those observed for TDB.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00194969
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  • 58
    Electronic Resource
    Electronic Resource
    A new isosorbide dinitrate extended-release formulation: pharmacokinetic and clinical parameters in patients with stable angina pectoris (1994)
    Springer
    European journal of clinical pharmacology 47 (1994), S. 351-354 
    Details
    ISSN: 1432-1041
    Keywords: Isosorbide dinitrate ; Angina pectoris ; pharmacokinetics ; clinical efficacy ; digital photoplethysmography
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract In a double-blind, cross-over study the acute clinical efficacy and pharmacokinetic profile of a newly developed isosorbide dinitrate extended-release (ISDN-ER) formulation (10 mg immediate release and 60 mg slow release) were examined in eight angina patients. Exercise tests were done 1 h before and 1, 6 and 10 h after acute ISDN or placebo; similar testing was repeated after 14 days of open-labelled treatment. At 1, 6 and 10 h after administration, ISDN-ER significantly reduced the mean ST depression at highest comparable workload (HCWL) by 0.8, 0.6, and 0.6 mm, respectively. Total exercise duration increased significantly by 46, 42 and 72 s. The rate-pressure product at HCWL was not reduced significantly at any time, while digital plethysmography demonstrated a significant effect on arterial pulse curves throughout the 10 h. After 14 days of once-daily treatment, similar or somewhat attenuated clinical effects were observed. Pharmacokinetic measurements showed a first peak of ISDN at 1–2 h and a second peak at 4–5 h. The 5-isosorbide mononitrate (5-ISMN) metabolite peaked at 5–8 h and remained high at 10 h. After 14 days of treatment, the mean plasma concentrations of ISDN and 5-ISMN before drug were 0 and 69 ng·ml−, respectively. Thus, satisfactory acute clinical efficacy and low nitrate levels during the night were observed. However, long-term clinical efficacy needs to be established in larger, placebo-controlled trials.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00191167
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  • 59
    Electronic Resource
    Electronic Resource
    Metabolism and pharmacokinetics of prostaglandin E1 administered by intravenous infusion in human subjects (1994)
    Springer
    European journal of clinical pharmacology 46 (1994), S. 275-277 
    Details
    ISSN: 1432-1041
    Keywords: Prostaglandin E1 ; Infusion ; pharmacokinetics ; metabolism ; volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract In a single-blind, randomized, two-way crossover study with 12 healthy male volunteers, 60 μg of prostaglandin E1 (PGE1) or placebo was administered by intravenous infusion during a 120-min period. PGE1, 13,14-dihydro-PGE1 (PGE0) and 15-keto-PGE0 plasma concentrations were measured by a highly specific and sensitive GC-MS/MS method. Endogenous PGE1 plasma concentrations ranged between 1.2 and 1.8 pg·ml−1. Endogenous PGE0 and 15-keto-PGE0 plasma concentrations varied from 0.8 to 1.3 pg·ml−1 and from 4.2 to 6.0 pg/ml respectively. During intravenous infusion of PGE1, plasma PGE1 concentrations rose to a level twice as high as during the placebo infusion. In contrast, PGE0 plasma concentrations were 8 times higher during PGE1 infusion than during placebo infusion, and 15-keto-PGE0 plasma concentrations were 20 times higher. The new analytical method has thus been useful to describe the pharmacokinetics of PGE1 and its metabolites PGE0 and 15-keto-PGE0, during and after intravenous infusion of PGE1.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00192562
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  • 60
    Electronic Resource
    Electronic Resource
    Effect of diet on the single- and multiple-dose pharmacokinetics of sustained-release ketoprofen (1994)
    Springer
    European journal of clinical pharmacology 47 (1994), S. 361-366 
    Details
    ISSN: 1432-1041
    Keywords: Ketoprofen ; diet ; bioavailability ; pharmacokinetics ; sustained release
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract The indirect effect of diet on the single-and multiple-dose pharmacokinetics of sustained-release ketoprofen was studied in 16 healthy male volunteers. In an open, cross-over design, 200 mg ketoprofen was administered as a gastric-juice-resistant, sustained-release tablet once daily during two periods of 5 days. A low-calorie/low-fat diet (LCFD) was given in the first period and a high-calorie/high-fat diet (HCFD) in the second period. The first meal on each day was given 4 h after drug intake. Ketoprofen plasma concentrations were measured over 24 h after the first dose on day 1 and over 36 h after the final dose on day 5 of each period. On average, plasma concentrations of ketoprofen were higher with the LCFD than with the HCFD. With the HCFD there was a tendency to longer absorption-lag times on day 5. The maximum concentration and the area under the curve over one 24-h dosage period (AUC0–24) were significantly higher with the LCFD, both on day 1 and on day 5. For AUC0–24 the differences were on average 15% (day 1) and 24% (day 5). The same tendency was observed for the amount excreted in urine over 24 h (Ae), but the difference was only significant on day 1 (14%). The elimination rate constant (Kβ) and the mean residence time were similar for the two diets, both on day 1 and on day 5. From these results, we conclude that there was an acute indirect effect of diet when a meal was had 4 h after intake of the medication. This resulted in a greater extent of ketoprofen absorption with the LCFD than with the HCFD. The absorption rate was apparently not influenced by this acute effect. The longer gastric residence time of ketoprofen with the HCFD may be the result of a long-term indirect effect on gastric emptying rate. If the extreme difference between the diets in this study is taken into account, it seems unlikely that the observed indirect effects have implications for clinical practice.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00191169
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  • 61
    Electronic Resource
    Electronic Resource
    Lack of interaction between ramipril and simvastatin (1994)
    Springer
    European journal of clinical pharmacology 47 (1994), S. 373-375 
    Details
    ISSN: 1432-1041
    Keywords: ACE-inhibitors ; Simvastatin ; ramipril ; lipid lowering drugs ; drug interaction ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Twenty two healthy males participated in a randomised, placebo-controlled, double blind, cross-over study to investigate the influence of simvastatin on the pharmacokinetics of ramipril and its active metabolite (ramiprilat), and on the ACE-inhibiting effect of ramiprilat. During two study periods, each of 7 days, subjects received daily either simvastatin 20 mg at 19.00 h or placebo; ramipril (5 mg) was given on Day 5 of each of the periods. Plasma concentrations of ramipril and ramiprilat and ACE-activity were measured in sequential blood specimens, and ramipril and ramiprilat concentrations were measured in urine. Blood and urine collections for pharmacokinetic and pharmacodynamic assessment were made up to 72 h after the dose of ramipril. The mean AUC of ramipril for ramipril+placebo (R+P) and ramipril+simvastatin (R+S) was 22.2 and 21.3 ng.h.ml−, respectively; for ramiprilat the corresponding figures were 61.3 and 57.6 ng.h.ml−. The urinary excretion of ramipril+metabolites for (R+P) and (R+S) was 25.2 and 24.1% of dose. The maximum percentage inhibition of ACE-activity for (R+P) was 94.6%, and for (R+S) it was 94.1%. It is concluded that concomitant administration of simvastatin and ramipril has no clinically relevant effect on the pharmacokinetics or ACE-inhibition of the latter drug and its metabolites.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00191171
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  • 62
    Electronic Resource
    Electronic Resource
    Disposition kinetics of buspirone in patients with renal or hepatic impairment after administration of single and multiple doses (1994)
    Springer
    European journal of clinical pharmacology 46 (1994), S. 41-47 
    Details
    ISSN: 1432-1041
    Keywords: Buspirone ; pharmacokinetics ; renal impairment ; hepatic impairment ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract The single dose and steady-state pharmacokinetics of buspirone and its metabolite 1-pyrimidinyl piperazine (1-PP) have been evaluated in normal volunteers and patients with renal or hepatic impairment, using a parallel group design, with assignment of patients to study group on the basis of the degree of renal (mild, moderate, severe) or hepatic (compensated or decompensated) impairment. Each healthy volunteer or patient received a single dose of 10 mg buspirone on Day 1 of the study, and starting 36 h after the first dose, healthy volunteers and patients received 10 mg doses of buspirone every 12 hours for 9 days. On the morning of Day 10 they received the last dose. Serial blood samples were collected on Days 1, 5 and 10 and plasma was analysed for buspirone and 1-PP. The plasma concentrations of buspirone and 1-PP were highly variable regardless of the renal or hepatic function. The peak concentrations (Cmax) and area under the curves (AUC) of buspirone and 1-PP on Days D 5 and 10 were higher than on Day D 1. The trough levels (Cmin) and AUCs (D 5 and 10) of buspirone and 1-PP indicated, that, regardless of renal or hepatic function, steady state was reached after 3 to 5 days of dosing. At steady-state, patients with renal or hepatic impairment had significantly higher Cmax and AUC values of buspirone than in normal volunteers. However, the intensity and frequency of adverse experiences in patients with renal or hepatic impairment were not significantly different from those observed in normal volunteers. There was no correlation between the average plasma concentrations of buspirone ( $$\bar C$$ ) and the degree of renal impairment judged by creatinine clearance. An excellent correlation was observed between $$\bar C$$ of buspirone and serum albumin (r=0.862, and P〈0.0001) as well as between $$\bar C$$ and bromsulphalein clearance (r=0.678, P〈0.0003). In view of high intra-and inter-subject variability in buspirone concentrations, definitive dosing recommendations for patients with compromised renal or hepatic function could not be made, but such patients should initially be dosed cautiously with buspirone.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00195914
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  • 63
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    Electronic Resource
    A comparative study of the steady-state pharmacokinetics of immediate-release and controlled-release diltiazem tablets (1994)
    Springer
    European journal of clinical pharmacology 46 (1994), S. 243-247 
    Details
    ISSN: 1432-1041
    Keywords: Diltiazem ; immediate-release tablet ; controlled-release tablet ; steady state ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract We have studied the controlled-release properties and relative systemic availabilities of two dosages of the same controlled-release (CR) diltiazem tablet formulation by comparing them at steady state with those of an immediate-release formulation. We measured 24-hour plasma concentration profiles during 4-day treatments with diltiazem 90 mg CR tablet bd diltiazem 120 mg CR tablet bd, and conventional diltiazem 60 mg immediate-release (IR) tablet tid. The study had a randomized, three-way crossover design. Twelve healthy men (38–52 y) participated. Trough plasma concentrations were determined on days 3 and 4. The 24-h plasma concentration-time profiles were assessed after the last morning dose on day 4 of each period. The following steady-state pharmacokinetic values were calculated: the minimum plasma concentration (Cmin), the maximum plasma concentration (Cmax), the time interval during which the plasma concentration exceeded 75% of Cmax (t75), the area under the plasma concentration-time curve (AUC72–96), the peak-to-trough fluctuation (PTF), and the area-under-the-curve fluctuation (AUCF). Steady state was achieved on day 3. The pharmacokinetics were comparable. For diltiazem CR 90 mg and diltiazem CR 120 mg, AUC84–96 (night) was approximately 75% of AUC72–84 (daytime). The diltiazem plasma concentration increased slowly from about 6 h after the evening dose of both CR tablets, resulting in relatively high plasma concentrations in the early morning hours. Only during treatment with diltiazem CR 120 mg were the plasma concentrations of diltiazem maintained above the minimum therapeutic plasma concentration of 50 μg·1−1 throughout the full 24 h. In conclusion, twice-daily treatment with diltiazem CR tablets can replace thrice-daily treatment with the conventional diltiazem IR tablet. The early morning rise of the diltiazem plasma concentration, which might lead to a lower incidence of ischaemic events, may be an important clinical advantage of both CR tablets. Because of the minimum therapeutic plasma concentration of 50 μg·1−1, twice-daily administration of the 120 mg CR tablet may be preferred from a therapeutic point of view. Diltiazem, a benzothiazepine, is a calcium antagonist used in the treatment of angina pectoris and hypertension. The anti-ischaemic mechanism of diltiazem seems to result from an increase of myocardial oxygen supply and a reduction in myocardial oxygen demand, respectively by coronary artery dilatation and/or direct and indirect haemodynamic effects, such as afterload reduction and heart rate decrease (Braunwald 1982). Its therapeutic effect is evident at daily dosages between 180 and 360 mg (Low et al. 1981). After oral administration it is almost completely absorbed from the gastrointestinal tract, but owing to extensive first-pass metabolism, its systemic availability is approximately 40–50% (Echizen and Eichelbaum 1986). The time to maximum plasma concentrations after oral administration of immediate-release formulations is approximately 3 to 4 h. The elimination half-life of diltiazem is 3.5–7 h, implying that frequent dosing is required to maintain effective plasma concentrations. Therefore, a controlled-release formulation of diltiazem, designed to be taken twice daily, has been developed. The aim of this crossover study was to compare the systemic availability and steady-state pharmacokinetics of a controlled-release diltiazem tablet formulation (90 and 120 mg) with those of a conventional diltiazem immediate-release tablet in healthy volunteers.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00192556
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    Cyclosporin pharmacokinetics in heart-lung transplant recipients with cystic fibrosis (1994)
    Springer
    European journal of clinical pharmacology 46 (1994), S. 261-265 
    Details
    ISSN: 1432-1041
    Keywords: Cystic fibrosis ; Cyclosporin ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Cyclosporin (CsA) is currently the main immunosuppressive agent used in organ transplantation with considerable improvement in graft survival. Oral CsA solution is highly lipophilic, and its bioavailability may be reduced in cystic fibrosis (CF) heart-lung transplant recipients with pancreatic, gastrointestinal, and hepatic insufficiency. The bioavailability of oral CsA solution in 7 CF transplant recipients (5 male and 2 female with a mean age of 27 years and a mean weight of 49 kg) and 3 non-CF heart-lung recipients (1 male and 2 female with a mean age of 41 years and a mean weight of 60 kg) was studied. Following intravenous CsA administration, the kinetic curves were similar with no significant difference in the volume of distribution and clearance of CsA demonstrated between the CF and non-CF groups. The mean daily dose of oral CsA in 7 CF subjects (23.3 mg·kg−1) was significantly higher than the 3 non-CF heart-lung recipients (4.8 mg·kg−1). The mean maximum blood concentration of CsA for the oral dose was 776 ng·ml−1 for the 7 CF subjects, which was comparable with the mean peak values of 789 ng·ml−1 for the 3 non-CF control subjects. Poor enteral absorption of CsA probably accounts for the significantly lower mean bioavailability in the 7 CF subjects (14.9%) compared with the 3 non-CF control subjects (39.4%). The effects on the bioavailability of oral CsA solution by pancreatic enzymes (Creon) and histamine-2 antagonist (ranitidine) were also evaluated in the 7 CF subjects. No significant difference was demonstrated.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00192559
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    Electronic Resource
    Population approaches in drug development (1994)
    Springer
    European journal of clinical pharmacology 46 (1994), S. 389-391 
    Details
    ISSN: 1432-1041
    Keywords: Population approach ; Drug development ; software ; pharmacokinetics ; pharmacodynamics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract An expert meeting to discuss population pharmacokinetic/pharmacodynamic software was held in Brussels in November 1993 under the auspices of the European Co-operation in Science and Technology (COST), Medicine (B1) programme. Recently developed statistical methods offer the possibility of gaining integrated information on pharmacokinetics and response from relatively sparse observational data obtained directly in patients who are being treated with the drug under development. These methods can minimize the need to exclude patient groups and also allow analysis of a variety of unbalanced designs that frequently arise in the evaluation of the relationships between dose or concentration on the one hand and efficacy or safety on the other relationships that do not readily lend themselves to other forms of statistical analysis. The purpose of the Brussels meeting was to evaluate the state of both existing software and software under development, and to specify the needs and wishes of potential users of such software. It was apparent from the meeting that software development for population data analysis is currently a very active area of investigation and that several very good packages are already available, with more in development. The general consensus of the meeting was that well validated, easy to use software was essential to the implementation of the population approach to drug development.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00191898
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  • 66
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    Electronic Resource
    Paracetamol pharmacokinetics during the first trimester of human pregnancy (1994)
    Springer
    European journal of clinical pharmacology 46 (1994), S. 451-454 
    Details
    ISSN: 1432-1041
    Keywords: Pregnancy ; Paracetamol ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Paracetamol pharmacokinetics was evaluated in groups of pregnant (8–12 weeks) and non pregnant women given the standard oral dose of 650 mg. The mean half-life was significantly lower and oral clearance was significantly higher in the first trimester group compared to the control group. The AUC was lower in the first trimester but the difference was not significant. The maximum serum concentration (Cmax) was reached 48 min after administration in both groups, and the mean maximal serum concentration was similar in the pregnant and non-pregnant women (11.16 and 11.58 μg·ml−1). A correlation of r=0.85 was found between Cmax and the weight of the pregnant women (P〈0.01) but not with the weight of the control women, this suggests that weight gain might be used to determine the women in whom dosage adjustment is needed.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00191910
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    The quinolone, flumequine, has no effect on theophylline pharmacokinetics (1994)
    Springer
    European journal of clinical pharmacology 46 (1994), S. 477-478 
    Details
    ISSN: 1432-1041
    Keywords: Theophylline ; flumequine ; drug interaction ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract The kinetics of a single i. v. dose of theophylline given either alone or with flumequine was studied in eight healthy volunteers. No statistically significant differences were observed in the pharmacokinetic parameters of theophylline (volume of distribution, elimination half-life, AUC, plasma clearance) following the two treatments. Pretreatment for 5 days with oral flumequine (400 mg, three times daily) had no significant effect on the disposition of a single i. v. dose of theophylline in healthy volunteers.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00191915
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  • 68
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    The effect of hyperglycaemia on the absorption of glibenclamide in patients with non-insulin-dependent diabetes mellitus (1994)
    Springer
    European journal of clinical pharmacology 47 (1994), S. 53-55 
    Details
    ISSN: 1432-1041
    Keywords: Glibenclamide ; Diabetes ; NIDDM ; absorption ; hyperglycaemia ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract We have studied the absorption of glibenclamide 10 mg as a single morning dose in 7 patients with non-insulin-dependent diabetes mellitus, comparing normoglycaemic and hyperglycaemic states. The maximal glibenclamide plasma concentrations were significantly higher in the normoglycaemic than in the hyperglycaemic state (448 vs 228 mg·1-1) and these peak concentrations were attained faster in normoglycaemia than in hyperglycaemia (3.7 vs 5 h). We conclude that the absorption of glibenclamide in the two states is different.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00193478
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  • 69
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    The effects of age and sex on the systemic (1994)
    Springer
    European journal of clinical pharmacology 47 (1994), S. 57-60 
    Details
    ISSN: 1432-1041
    Keywords: Butorphanol ; transdermal ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract We have studied the effects of age and sex on the pharmacokinetics and the systemic availability of transnasal butorphanol in a randomized, two-way, crossover study of 48 subjects: young men and women, and elderly men and women. Each subject took a single 1 mg dose of intravenous and transnasal butorphanol tartrate on separate occasions with a one-week washout period. Blood samples were collected over 16 hours. Plasma butorphanol concentrations were determined using radioimmunoassay. The AUC of plasma butorphanol concentrations after an intravenous injection were higher in the elderly women than in the other groups. However, there were no significant differences in Cmax and AUC between the groups after transnasal administration. The mean systemic availability of transnasal butorphanol was about 70 %, except for the elderly women (48 %). After intravenous and transnasal administration, the half-life and mean residence time were greater in the elderly than the young. Clearance was lower in women than men. Apparent volume of distribution was higher for elderly men than the others. The age- and sex-related changes in the pharmacokinetics of transnasal butorphanol are not large enough to necessitate dosage differences.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00193479
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  • 70
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    Electronic Resource
    Cyclosporine pharmacokinetics in nephrotic and kidney-transplanted children (1994)
    Springer
    European journal of clinical pharmacology 47 (1994), S. 61-65 
    Details
    ISSN: 1432-1041
    Keywords: Cyclosporine A ; kidney transplant ; nephrotic syndrome ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract The pharmacokinetic parameters of cyclosporine (CsA) were determined in 23 kidney transplant recipients and 19 children with nephrotic syndrome, after intravenous and oral administration. The mean bioavailability was 39 %, blood clearance was 0.55 l · h-1 · kg-1 and volume of distribution at steady-stade was 2.77 l · kg-1. The absorption profile was monophasic (67 %), biphasic (29 %) or poor (4 %). The maximum blood concentration of CsA was significantly higher in children with a monophasic profile than in children with a biphasic profile (550 vs 380 ng · ml-1). Blood clearance was significantly higher in the transplant recipients than in the patients with nephrotic syndrome (0.65 vs 0.43 l · h-1 · kg-1. Although age, haematocrit, creatinine clearance, serum albumin and cholesterol differed between the two groups, only haematocrit and creatinine clearance were significantly (negatively) correlated with CsA clearance.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00193480
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  • 71
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    The effect of food on the interaction of ofloxacin with sucralfate in healthy volunteers (1994)
    Springer
    European journal of clinical pharmacology 47 (1994), S. 67-69 
    Details
    ISSN: 1432-1041
    Keywords: Ofloxacin ; sucralfate ; food ; drug interaction ; absorption ; healthy volunteers ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract We have studied the effect of food on the interaction of ofloxacin with sucralfate. Six healthy men took a single oral dose of ofloxacin (200 mg) on 4 occasions: alone after overnight fasting or after breakfast (non-fasting), and with sucralfate fasting or non-fasting. There were no significant differences in the plasma concentration-time profiles of ofloxacin after ofloxacin alone between fasting and non-fasting conditions. On the other hand, the peak plasma concentration and AUC of ofloxacin after co-administration with sucralfate while fasting fell by 70 and 61 % compared with ofloxacin alone; the changes non-fasting were 39 and 31 % respectively. The interaction of ofloxacin with sucralfate was markedly reduced by food, but still could not be disregarded.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00193481
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  • 72
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    Plasma levels of oxybutynine chloride in children (1994)
    Springer
    European journal of clinical pharmacology 46 (1994), S. 83-85 
    Details
    ISSN: 1432-1041
    Keywords: Enuresis ; Oxybutynine chloride ; children ; pharmacokinetics ; adverse effects ; anticholinergic actions
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Anticholinergic adverse-effects in children treated with conventional doses of oxybutynine led us to measure plasma oxybutynine levels in children. 18 children, aged 5 to 13 y, who required treatment with oxybutynine chloride for daytime incontinence were studied. Plasma concentrations were measured on the fifth day of a course of treatment in which the dose was adapted to the child's body weight; the dose was given twice daily at 12-hour intervals. In 10 children aged between 5 and 8 y, the mean dose was 0.1 mg · kg−1. In 8 children aged between 10 and 13 years, the mean dose was 0.15 mg · kg−1. The highest concentration was usually found between 1 and 2 h after administration. The subsequent fall in concentration was rapid and after 6 h oxybutynine was no longer measurable in 14 of the children. The concentrations found were not different from those seen in adults given equivalent doses. The results show that plasma concentrations in children were not very different from those observed in adults if the dose were adapted to the body weight of the children. No special differences in paediatric use were revealed that might explain the particular adverse-effects. The results of the study argue against the dosage regimen proposed before these adverse events were detected. They strongly favour a dose adapted to the body weight of the child, with a 12-hour interval between doses.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00195921
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  • 73
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    Plasma concentrations and effect on testosterone metabolism after single doses of MK-0434, a steroid 5 alpha-reductase inhibitor, in healthy subjects (1994)
    Springer
    European journal of clinical pharmacology 46 (1994), S. 123-126 
    Details
    ISSN: 1432-1041
    Keywords: Steroid 5α-reductase inhibitor ; Testosterone metabolism ; MK-0434 ; pharmacodynamics ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract A four-period, two-panel, single-rising-dose study (0.1–100 mg) was conducted in healthy males to investigate the pharmacodynamics, tolerability and pharmacokinetics of MK-0434, a steroid 5α-reductase inhibitor. MK-0434 was associated with a significant reduction in dihydrotestosterone, which was maximal at 24 h and maintained through 48 h post treatment. The maximum reduction was approximately 50 % and occurred at all doses above 5 mg (10, 25, 50 and 100 mg). MK-0434 appeared to have no effect on serum testosterone at these single doses. Rising single doses of MK-0434 were associated with an increase in Cmax and AUC but the changes were less than proportional to dose, most likely due to nonlinear absorption. MK-0434 given in single doses up to 100 mg was without significant adverse effects in healthy male volunteers. In summary, MK-0434 is a well-tolerated, potent, orally active 5α-reductase inhibitor in man.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00199874
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  • 74
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    Influence of concomitant food intake on the oral absorption of two triazole antifungal agents, itraconazole and fluconazole (1994)
    Springer
    European journal of clinical pharmacology 46 (1994), S. 147-150 
    Details
    ISSN: 1432-1041
    Keywords: Fluconazole ; Itraconazole ; pharmacokinetics ; food interaction ; gastric emptying time ; pH radiocapsule
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract The influence of food on the pharmacokinetics of the triazole antimycotics fluconazole and itraconazole was investigated in a randomised, parallel group, single dose study in 24 healthy subjects. Each group took either a 100 mg capsule of fluconazole or a 100 mg capsule of itraconazole, pre-prandially or after a light meal or a full meal, in a three-way crossover design. Gastric and intestinal pH were measured with a co-administered radio-telemetric pH capsule, and gastric emptying time of the capsule (GET) was taken as the maximum gastric residence time of drug and food. The plasma AUC and Cmax of itraconazole were significantly different under the various conditions and the mean AUC was greatest after the full meal. The bioavailability (90% confidence intervals) of itraconazole relative to that after the full meal, was 54% (41–77%) on an empty stomach and 86% (65–102%) after a light meal. The criteria for bioequivalence were not attained. In contrast, the bioavailability (90% CI) of fluconazole relative to the full meal was 110% pre-prandially (100–115%) and 102% after the light meal (88–103%), and the criteria for bioequivalence were attained. Itraconazole absorption was promoted by low stomach pH, long gastric retention time and a high fat content of the coadministered meal, whereas the pharmacokinetics of fluconazole was relatively insensitive to physiological changes in the gastrointestinal tract.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00199879
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  • 75
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    Electronic Resource
    Pharmacokinetics and tolerability of ascending intravenous doses of granisetron, a novel 5-HT3 antagonist, in healthy human subjects (1994)
    Springer
    European journal of clinical pharmacology 46 (1994), S. 159-162 
    Details
    ISSN: 1432-1041
    Keywords: Granisetron ; Anti-emetic ; pharmacokinetics ; tolerance ; ascending dose ; healthy subjects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract The pharmacokinetics and tolerance of granisetron, a novel 5HT3-receptor antagonist which is under development as an anti-emetic agent have been studied after administration of single 30 min intravenous infusions to three groups of 8 healthy male subjects, in a series of placebo-controlled ascending dose studies (50, 80, 100 and 130 μg·kg−1 to group 1; 150, 180, 200 and 230 μg·kg−1 to group 2 and 270 and 300 μg·kg−1 to group 3). Plasma and urine samples were analysed for granisetron by HPLC with fluorimetric detection. Administration of granisetron was well tolerated by the volunteers and there were no serious adverse effects reported. Pharmacokinetic parameters and dose-normalised plasma levels appeared to be independent of dose in the range 50 to 300 μg·kg−1, although there was extensive inter-subject variability. Granisetron was extensively distributed, with mean volumes of distribution ranging from 186–264 l at the various doses. Total plasma clearance was, in general, rapid (mean values of 37.0 to 49.9 l·h−1) and predominantly non-renal, with most subjects excreting less than 20% of the dose unchanged in urine. Mean t1/2 values ranged from 4.1 to 6.3 h and MRT from 5.2 to 8.1 h.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00199881
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  • 76
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    Pharmacokinetics and dosage recommendations of teicoplanin in patients treated by continuous veno-venous haemodialysis (CVVHD) (1994)
    Springer
    European journal of clinical pharmacology 46 (1994), S. 179-180 
    Details
    ISSN: 1432-1041
    Keywords: Teicoplanin ; haemodialysis ; renal failure ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00199886
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  • 77
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    Pharmacokinetics of torasemide and its metabolites in end-stage renal disease (1994)
    Springer
    European journal of clinical pharmacology 47 (1994), S. 157-159 
    Details
    ISSN: 1432-1041
    Keywords: Torasemide ; metabolites ; end-stage renal disease ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract The pharmacokinetics of torasemide, a new loop diuretic, as well as its active metabolites M1 and M3, and its inactive main metabolite, M5, were studied in 12 patients with end-stage renal failure during single i.v. (n=6) or single oral (n=6) dosing of 200 mg torasemide, and during chronic oral treatment for 9 days (n=12). The elimination half-life (t1/2) of torasemide was unchanged in renal failure, whereas t1/2 of the torasemide metabolites M1, M3, and M5 were markedly prolonged. However t1/2 as well as the area under the plasma level time curve of torasemide and its metabolites were unchanged during chronic compared to acute administration. The results of this study suggest that despite the increased half-life of torasemide metabolites M1, M3 and M5 in end-stage renal failure patients, no accumulation of the parent drug torasemide and its metabolites during chronic dosing is demonstrable.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00194966
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    The effect of renal impairment on the pharmacokinetics of oxcarbazepine and its metabolites (1994)
    Springer
    European journal of clinical pharmacology 47 (1994), S. 161-167 
    Details
    ISSN: 1432-1041
    Keywords: Oxcarbazepine ; 10,11-dihydro-10-hydroxy-carbamazepine ; renal impairment ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract We have studied the effect of renal impairment on the pharmacokinetics of oxcarbazepine, its active monohydroxy-metabolite (which predominates in plasma), their glucuronides, and the inactive dihydroxy-metabolite after a single oral dose of oxcarbazepine (300 mg). Six subjects with normal renal function and 20 patients with various degrees of renal impairment participated. The mean areas under the plasma concentration-time curves of oxcarbazepine and its monohydroxy-metabolite were 2–2.5-times higher in patients with severe renal impairment (CLCR〈10 ml·min−1) than in healthy subjects. The apparent elimination half-life of the monohydroxy-metabolite [19 (SD 3) h] in these patients was about twice that in healthy subjects. The effect of renal impairment on the plasma concentrations of glucuronides was more marked. The renal clearances of the unconjugated monohydroxy-metabolite and its glucuronides (the main compounds recovered in urine) correlated well with creatinine clearance. The maximum target dose in patients with slight renal impairment (CLCR〉30 ml·min−1) should not be changed. In patients with moderate renal impairment (CLCR10–30 ml·min−1) it should be reduced by 50%. In patients with severe renal impairment (CLCR〈10 ml·min−1), the glucuronides of oxcarbazepine and its monohydroxy-metabolite are likely to accumulate during repeated administration, and dosage adjustment of oxcarbazepine in these patients could not be proposed from this single administration study.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00194967
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    Pharmacokinetics of intravenous omeprazole in children (1994)
    Springer
    European journal of clinical pharmacology 47 (1994), S. 181-185 
    Details
    ISSN: 1432-1041
    Keywords: Omeprazole ; pharmacokinetics ; children ; genetic polymorphism
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract This study was undertaken to define the pharmacokinetics of omeprazole in children and included 13 patients, heterogenous in terms of age (0.3 to 19 years), underlying disease and biological constants, indication of omeprazole administration and associated therapy. The dose administered ranged from 36.9 to 139 mg·1.73 m−2. The pharmacokinetic parameters of omeprazole were: systemic clearance, 0.23 1·kg−1·h−1; volume of distribution, 0.45 1·kg−1; elimination half life 0.86 h; but were highly variable between individuals. Dosage, differences in hepatic and renal function and associated therapy may contribute to inter-individual variability. Within the range of doses administered, the pharmacokinetic parameters were similar to those reported in adults. The drug has been well tolerated in all children.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00194970
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  • 80
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    Weighted serum pools in comparison to the trapezoidal rule for estimating AUCs for ethinyl estradiol (1994)
    Springer
    European journal of clinical pharmacology 46 (1994), S. 77-81 
    Details
    ISSN: 1432-1041
    Keywords: Trapezoidal rule ; Ethinyl estradiol ; variance components ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract The concept of a weighted pool for estimating the area under the curve (AUC) is presented and set in relationship to the trapezoidal rule. An example from a pharmacokinetic study on ethinyl estradiol is used to demonstrate the use of variance component analysis for relating the intraindividual variance of the AUC, trapezoidal rule and weighted pool to the variance of the determination process. Depending on the sampling times, the theoretical variance of the weighted pool is greater than the theoretical variance of the trapezoidal rule. In the example presented, it was shown that this difference is of no importance in relation to the interindividual variance of the AUC, which dominates the total variance. In the example study, routine quality control samples were also determined in each assay, which allowed independent confirmation of the discussed results on the intraindividual variance of the AUCs.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00195920
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    Doxycycline carrageenate — an improved formulation providing more reliable absorption and plasma concentrations at high gastric pH than doxycycline monohydrate (1994)
    Springer
    European journal of clinical pharmacology 46 (1994), S. 143-146 
    Details
    ISSN: 1432-1041
    Keywords: Doxycycline ; bioavailability ; pH dependent absorption ; pharmacokinetics ; carrageenate ; adverse events
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract The effect of increased gastric pH (obtained by pre-treatment with omeprazole) on the bioavailability of doxycycline monohydrate and doxycycline carrageenate has been investigated in 24 healthy volunteers, using an open, randomised, four-treatment, four-period, crossover, 2×2 factorial design. Each subject received a single dose of 100 mg of each of the doxycycline formulations with and without pre-treatment with omeprazole (40 mg daily for 7 days). The two formulations were bioequivalent (rate and extent) during fasting without omeprazole pre-treatment, whereas after omeprazole, the monohydrate showed a highly significant decrease in bioavailability (38% for AUC and 45% for Cmax) compared to the carrageenate formulation, which was not affected by prior administration of omeprazole. Many of the subjects did not reach a therapeutic plasma level of doxycycline during the combination of omeprazole and doxycycline monohydrate, and most adverse events (mainly gastrointestinal) were reported after this combination. As large populations of patients have a high gastric pH due to frequent use of H2-blockers, proton pump inhibitors and antacids, as well as to physiological achlorhydria, the decreased absorption of doxycycline monohydrate may well have a clinical impact, for example when the patients are treated with tetracyclines for an infection.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00199878
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  • 82
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    Electronic Resource
    Inhibition of soluble catechol-O-methyltransferase and single-dose pharmacokinetics after oral and intravenous administration of entacapone (1994)
    Springer
    European journal of clinical pharmacology 46 (1994), S. 151-157 
    Details
    ISSN: 1432-1041
    Keywords: Entacapone ; catechol-O-methyltransferase ; pharmacokinetics ; healthy volunteers ; adverse effects ; metabolism
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract The inhibition of soluble catechol-O-methyltransferase (S-COMT) in red blood cells (RBCs) by entacapone, and the pharmacokinetics of entacapone after single oral (5–800 mg) and IV (25 mg) doses have been examined in an open study in 12 healthy young male volunteers. Oral entacapone dose-dependently decreased the activity of S-COMT in RBCs with a maximum inhibition of 82% after the highest dose (800 mg). The inhibition of S-COMT in RBCs was reversible and the activity recovered within 4–8 h. Entacapone showed linear pharmacokinetics over the dose range studied: Cmax and AUC were correlated with the dose of the drug. Oral absorption of entacapone was fast, with a tmax ranging from 0.4 to 0.9 h, depending on the dose. Systemic availability of entacapone varied between 30 and 46%. Entacapone was rapidly eliminated by metabolism with a half-life of 0.27–0.30 h after oral doses of 5 to 50 mg. After doses from 100 to 800 mg the disposition was best described by two phases with a t1/2α of 0.27–0.37 h and t1/2β of 1.59–3.44 h. Over the dose range studied, the single oral and IV doses of entacapone were well tolerated. No haematological, biochemical or haemodynamic adverse effects were seen. The results show that entacapone is an orally effective and reversible COMT inhibitor in man and has simple, linear pharmacokinetics.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00199880
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  • 83
    Electronic Resource
    Electronic Resource
    The pharmacokinetics and pharmacodynamics of medifoxamine after oral administration in healthy elderly volunteers (1994)
    Springer
    European journal of clinical pharmacology 46 (1994), S. 163-166 
    Details
    ISSN: 1432-1041
    Keywords: Medifoxamine ; pharmacokinetics ; pharmacodynamics ; elderly volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract The pharmacokinetics and psychomotor effects of medifoxamine, a 5 HT reuptake inhibitory antidepressant, were studied in healthy elderly volunteers after single and multiple dosing. The elimination half life (t1/2z) after single doses of 300 mg was 2.8 h — almost identical to that found in young volunteers. After seven days of dosing at 100 mg three times daily the mean corrected AUC after 300 mg significantly increased from 1.04 to 1.34 mg.h.l−1 and t1/2z increased to 4.0 h (NS). There were no significant changes in critical flicker fusion frequency, symbol digit substitution, continuous attention or choice reaction times.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00199882
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  • 84
    Electronic Resource
    Electronic Resource
    The effect of renal function on the pharmacokinetics of ranitidine (1994)
    Springer
    European journal of clinical pharmacology 46 (1994), S. 167-171 
    Details
    ISSN: 1432-1041
    Keywords: Ranitidine ; Renal impairment ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract This open study evaluated the influence of renal function on the pharmacokinetics of ranitidine (50 mg iv infusion given over 6 min). Five groups, each of 8 subjects, 1 with normal renal function and 4 with different degrees of renal impairment were studied. Renal function was assessed in each patient by 51Cr-EDTA (glomerular filtration rate, GFR), creatinine clearance (GFR) and N-methylnicotinamide clearance (reflecting glomerular and tubular function). Sixteen blood samples (5 ml) taken up to 48 h post dose from each subject were analysed for plasma ranitidine concentrations by reversed phase HPLC. Patient groups with renal impairment had significantly increased AUC∞ and t1/2 with corresponding decreases in CLp and λz when compared with normal subjects. There was also a significant increase in tmax but not in Cmax. There was a high linear correlation between the degree of renal impairment and ranitidine clearance. In patients with GFR ≤ 20 ml min−1, the AUC∞ mean ratio (compared with normal subjects) was up to 4.6 while for patients with GFR 20–50 ml min−1, the average AUC∞ ratio was 2.6. It is recommended that the dose of ranitidine is halved in patients with GFR ≤ 20 ml min−1.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00199883
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  • 85
    Electronic Resource
    Electronic Resource
    Influence of input rates on (±)-isradipine haemodynamics and concentration-effect relationship in healthy volunteers (1994)
    Springer
    European journal of clinical pharmacology 46 (1994), S. 29-33 
    Details
    ISSN: 1432-1041
    Keywords: Israpidine ; haemodynamics ; pharmacokinetics ; healthy volunteers ; drug input rate
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Since the magnitude of the response to a drug may depend upon the drug input rate, the concentration-effect relationship of the new dihydropyridine (±)-isradipine was investigated using different administration modalities. Ten normotensive healthy volunteers were given, double-blind and in a crossover fashion, isradipine as a 1 mg iv infusion, 5 mg oral solution, 5 mg standard tablet, 10 mg slow release formulation, and a placebo. Blood pressure, heart rate, and plasma isradipine concentrations were recorded for 24 h. The maximal fall in diastolic blood pressure was similar after the infusion (-11.40 mmHg), the oral solution (-15.20 mmHg), and the standard tablet (-12.50 mmHg). In healthy volunteers the slow release form had no significant effect on blood pressure. The concentration-effect plots showed an increasing slope in the order infusion, solution, and tablet, and anticlockwise hysteresis. This was partly due to marked heart rate counter-regulation, the corresponding mean maximal heart rate increases being 24, 19, and 17 beats·min−1. The pronounced counter-regulation of the heart rate implies that a slow isradipine input rate would be more effective in decreasing blood pressure.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00195912
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  • 86
    Electronic Resource
    Electronic Resource
    Kinetic interaction between theophylline and a newly developed anti-allergic drug, pemirolast potassium (1994)
    Springer
    European journal of clinical pharmacology 46 (1994), S. 55-58 
    Details
    ISSN: 1432-1041
    Keywords: Pemirolast ; Asthma ; theophylline ; drug interaction ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract The effect of a newly developed anti-allergic drug, pemirolast potassium (TBX), on the pharmacokinetics and metabolism of theophylline was investigated under steady-state conditions in seven healthy male volunteers. A sustained-release theophylline formulation (100 mg twice daily at 12 h intervals) was given as monotherapy and coadministered with TBX (10 mg twice daily at 12 h). Plasma concentration-time curves and the urinary excretion of theophylline and its major metabolites after administration of theophylline alone and after coadministration with TBX were compared. No significant adverse effects from this study were observed. There were no significant differences in the total body clearance, renal clearance and maximum concentration of theophylline between the two treatments, although coadministration of TBX significantly delayed the time to reach maximum concentration of theophylline. In the case of urinary excretion, no significant changes in the fraction of urinary excretion of theophylline and its metabolites were observed. These results indicate that TBX has little or no effect on the pharmacokinetics and metabolism of theophylline and suggest that TBX is safe for asthma patients receiving theophylline therapy for treatment of chronic obstructive airway diseases.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00195916
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  • 87
    Electronic Resource
    Electronic Resource
    Receptor binding assays in analysing the bioavailability and pharmacodynamic bioequivalence of active drug moieties (1994)
    Springer
    European journal of clinical pharmacology 46 (1994), S. 237-242 
    Details
    ISSN: 1432-1041
    Keywords: Metoprolol ; bioavailability ; bioequivalence ; receptor binding assay ; pharmacokinetics ; sustained release formulation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract The bioavailability and pharmacodynamic bioequivalence of a conventional and an experimental sustained-release formulation of 100 mg metoprolol tartrate were studied in a randomised cross-over study in seven healthy volunteers by assessing over 24 h the plasma kinetics of R,S-metoprolol, its β1-adrenoceptor binding component, and by determining the extent to which the active drug moiety in plasma occupied rabbit lung β1-and rat reticulocyte β2-adrenoceptors. The formulations differed markedly in their kinetic characteristics: the peak plasma concentration (Cmax) of R,S-metoprolol after administration of the conventional formulation was 140 ng·ml−1, (n=7) and it was approximately one-third of that after the sustained-release formulation, 49 ng·ml−1, (n=6); the AUC0–24 h-values for the formulations were 700 and 310 ng·h·ml−1, respectively. The Cmax for the β1-adrenoceptor binding component of metoprolol was 180 ng·ml−1 (n=7) after administration of the conventional, and 74 ng·ml−1 after administration of the sustained-release formulation. The corresponding AUC0–24 h-values for the receptor binding component were 920 and 470 ng·h·ml−1 (n=7). Thus, the kinetic differences between R,S-metoprolol and the β1-receptor binding component were considerable and they were affected by the type of formulation. In general, after administration of the sustained-release formulation, the percentage β1- and β2-adrenoceptor occupancy of metoprolol in plasma was 5–15% less than after administration of the conventional formulation. At 0.5–1.5 h after drug intake the average β1-adrenoceptor occupancy of the conventional formulation varied between 80–90% and that of the sustained release formulation between 20–76%. At these times the differences in receptor occupancy were significant; at 0.5–2 h after drug intake the average β2-adrenoceptor occupancy of the conventional formulation varied from 20–30%, and that of the sustained-release formulation was 2–17%. At other times the difference in receptor occupancy between the formulations was not significant. The results demonstrate that plasma concentration-kinetics were more discriminating than β-adrenoceptor-binding in analysing bioequivalence. It was possible to determine the bioavailability of the active ingredient of metoprolol and to study pharmacodynamic bioequivalence by using receptor binding assays.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00192555
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  • 88
    Electronic Resource
    Electronic Resource
    Whole blood concentrations of mefloquine enantiomers in healthy Thai volunteers (1994)
    Springer
    European journal of clinical pharmacology 47 (1994), S. 85-87 
    Details
    ISSN: 1432-1041
    Keywords: Mefloquine ; Enantiomers ; pharmacokinetics ; stereoselectivity
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract We studied the pharmacokinetics of the enantiomers of mefloquine in whole blood in healthy Thai volunteers after administration of a single oral dose of 750 mg of the racemic mixture. Mefloquine pharmacokinetics were stereoselective. The peak concentrations and areas under the curve of the (−) enantiomer were significantly higher than those of its antipode (0.79 versus 0.46 μg · ml-1 and 402 versus 94 μg · h · ml-1). The half-lives of (−)MQ were significantly longer than those of (+)MQ (531 versus 206 h). No stereoselectivity was observed for tmax values.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00193485
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  • 89
    Electronic Resource
    Electronic Resource
    Pharmacokinetics and haemodynamic effects of ISDN following different dosage forms and routes of administration (1994)
    Springer
    European journal of clinical pharmacology 46 (1994), S. 319-324 
    Details
    ISSN: 1432-1041
    Keywords: Isosorbide dinitrate ; route of administration ; isosorbide-5-mononitrate ; finger pulse wave ; pharmacokinetics ; haemodynamic effects ; plasma nitrates
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract The pharmacokinetics and haemodynamic effects of isosorbide dinitrate (ISDN) have been investigated following administration of single doses as a sublingual (SL) spray (2.5 mg), sublingual tablet (5 mg) and peroral tablet (10 mg) in a randomised, placebo-controlled double-blind cross-over trial in 16 healthy volunteers. After the sublingual spray Cmax was higher (39.0 ng·ml-1) and tmax was shorter (3.9 min) than after the sublingual (22.8 ng·ml-1 and 13.8 min) and peroral (16.9 ng·ml-1 and 25.6 min) tablets. The AUC of ISDN did not differ following any of the three formulations (1031; 879; 997 ng·ml-1·min, for the spray, SL tablet and PO-tablet, respectively). Mononitrate metabolites of ISDN (IS-2-MN and IS-5-MN) and total nitrates in plasma increased in proportion to the administered dose. This indicates that the fraction of the dose absorbed was the same for all the formulations but that the extent of first-pass metabolism increased in the order sublingual spray 〈 sublingual tablet 〈 peroral tablet. Thus, compared to the spray, the relative bioavailability of ISDN was 48% and 28% from the sublingual and peroral tablets, respectively. The haemodynamic effects were quantified using the a/b ratio of the finger pulse wave and the systolic blood pressure and heart rate under orthostatic conditions. For the a/b ratio of the finger pulse, the maximal effect was higher (emax=130%) and the time to emax (temax) shorter (16.6 min) after the spray than the sublingual tablet (84.4% and 25.5 min) or peroral tablet (90.2 and 31.3 min). The onset of effect was within 3, 5 and 7.5 min after the spray, sublingual and peroral tablets, respectively. A larger change in the orthostatically-induced decrease in systolic blood pressure and increase in heart rate was obtained following peroral than sublingual administration despite the similar plasma concentrations of ISDN. This probably reflects the larger amount of pharmacodynamically active mononitrate metabolites formed after oral dosing. The integrated effect following administration of 2.5 mg ISDN as spray was similar to that of a sublingual tablet of 5 mg.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00194399
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  • 90
    Electronic Resource
    Electronic Resource
    Pharmacokinetics and pharmacodynamics of lisinopril in advanced renal failure (1994)
    Springer
    European journal of clinical pharmacology 46 (1994), S. 537-543 
    Details
    ISSN: 1432-1041
    Keywords: Lisinopril ; Dose adjustment ; ACE inhibitors ; pharmacokinetics ; pharmacodynamics ; renal failure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract To prevent drug accumulation and adverse effects the dose of hydrophilic angiotensin-converting enzyme (ACE) inhibitors, e. g. lisinopril, must be reduced in patients with renal failure. To obtain a rational basis for dose recommendations, we undertook a prospective clinical trial. After 15 days of lisinopril treatment pharmacokinetic and pharmacodynamic parameters were determined in patients with advanced renal failure (n=8; endogenous creatinine clearance [CLCR]: 18 ml·min−1·1.73m−2) and in healthy subjects with normal renal function (n=16; CLCR: 107 ml·min−1·1.73m−2). The volunteers received 10 mg lisinopril once daily, the daily dose in patients (1.1–2.2 mg) was adjusted to the individual CLCR according to the method of Dettli [13]. After 15 days of lisinopril treatment the mean maximal serum concentration (C max) in patients was lower than in volunteers (30.7 vs 40.7 ng·ml−1, while the mean area under the concentration-time curve (AUC 0–24 h) was higher (525 vs 473 ng·h−1·ml−1). ACE activity on day 15 was almost completely inhibited in both groups. Plasma renin activity, angiotensin I and angiotensin II levels documented marked inhibition of converting enzyme in volunteers and patients. Furthermore, average mean arterial blood pressure in patients decreased by 5 mmHg and proteinuria from 3.9–2.7 g per 24 h after 15 days of treatment with the reduced dose of lisinopril. Adjustment of the dose of lisinopril prevents significant accumulation of the drug in patients with advanced renal failure during chronic therapy. Mean serum levels did not exceed this in subjects with normal renal function receiving a standard dose. Despite substantial dose reduction, blood pressure and proteinuria decreases were observed.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00196112
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  • 91
    Electronic Resource
    Electronic Resource
    Pharmacokinetics and pharmacodynamics of ramipril and piretanide administered alone and in combination (1994)
    Springer
    European journal of clinical pharmacology 46 (1994), S. 545-550 
    Details
    ISSN: 1432-1041
    Keywords: Ramipril ; Piretanide ; pharmacokinetics ; pharmacodynamics ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract The pharmacokinetics and pharmacodynamics of single oral doses of 5 mg ramipril and 6 mg piretanide administered separately and in combination were determined in a single blind, randomised, 3-period cross-over study in 24 healthy male volunteers. The peak plasma concentrations of ramipril and ramiprilat increased slightly (from 11.9 to 14.8 ng/ml, and from 6.39 to 8.96 ng/ml, respectively) as did the area under the plasma concentration-time curve of ramipril (0–4 h) and ramiprilat (0–24 h) (from 15.8 to 19.8 ng·ml−1·h, and from 63.4 to 74.6 ng·ml−1·h, respectively). The urinary excretion of ramiprilat also rose (from 6.82 to 7.73 % of dose) following simultaneous treatment with piretanide. These effects were probably due to reduced first-pass metabolism of ramipril/ramiprilat to inactive metabolites. The blood pressure lowering effect, the time course of inhibition of ACE activity in plasma and the concentration-response relationship for the inhibition of plasma ACE activity were not affected by piretanide. The peak plasma concentration of piretanide was somewhat reduced (from 285 to 244 ng/ml) following simultaneous treatment with ramipril. No other pharmacokinetic parameter was affected. Piretanide increased urine flow, and sodium, chloride and potassium excretion, especially during the first 2 hours following administration. These pharmacodynamic parameters were not affected by ramipril. Thus, simultaneous administration of single oral doses of ramipril and piretanide caused modest changes in the peak and average plasma concentrations of both drugs, which did not lead to detectable alterations in the pharmacodynamic parameters measured in healthy volunteers.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00196113
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  • 92
    Electronic Resource
    Electronic Resource
    A pharmacokinetic interaction between roxithromycin and midazolam (1994)
    Springer
    European journal of clinical pharmacology 46 (1994), S. 551-555 
    Details
    ISSN: 1432-1041
    Keywords: Midazolam ; Roxithromycin ; drug interaction ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract The interaction between roxithromycin and midazolam was investigated in a double-blind, randomised crossover study of two phases. Ten healthy volunteers were given roxithromycin (300 mg) or placebo once daily for 6 days. On the sixth day they ingested 15 mg midazolam. Plasma samples were collected and psychomotor performance measured for 17 h. Roxithromycin administration significantly increased the area under the plasma midazolam concentration-time curve from 8.3 to 12.2 ώg·ml−1·min and the elimination half-lives from 1.7 to 2.2 h. In psychomotor performance only minor differences were seen between the treatments in one of the measured psychomotor parameters. Thus, in contrast to the strong interaction between erythromycin and midazolam, the interaction between roxithromycin and midazolam appears less likely to be clinically significant.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00196114
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  • 93
    Electronic Resource
    Electronic Resource
    Protein binding of 2-chloro 2′-deoxyadenosine (cladribine) in healthy subjects and in patients with leukaemia (1994)
    Springer
    European journal of clinical pharmacology 46 (1994), S. 563-564 
    Details
    ISSN: 1432-1041
    Keywords: 2-Chloro-2′-deoxyadenosine (CdA) ; Protein binding ; Cladribine ; pharmacokinetics ; leukaemia
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract The plasma protein binding of 2-chloro-2′-deoxyadenosine (CdA) at 37°;C was studied by ultrafiltration in 5 healthy volunteers, in 11 patients with haematological malignancies and in purified protein preparations. In the patients, the binding of CdA to plasma proteins was 25.0% and in healthy subjects it was 21.1%. In a solution of human serum albumin (40 g·1−1), 24.3% CdA was bound, but less than 5% was bound in a solution of α1-acid-glycoprotein (0.7 g·1−1). No dependence of binding on the concentration of CdA was found within a range 25–1000 nmol·1−1. In conclusion, due to its limited binding to plasma proteins, any change in the binding of CdA is unlikely to have a major influence on its pharmacological effect.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00196117
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  • 94
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    Electronic Resource
    Effect of saliva flow rate on saliva phenytoin concentrations: implications for therapeutic monitoring (1994)
    Springer
    European journal of clinical pharmacology 46 (1994), S. 565-567 
    Details
    ISSN: 1432-1041
    Keywords: Phenytoin ; Saliva ; therapeutic drug monitoring ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract The effect of atropine-induced reductions in saliva flow rate on saliva phenytoin concentrations were evaluated in a randomised placebo-controlled crossover study in a group of epileptic patients stabilised on the drug. Pretreatment with atropine caused significant reductions in saliva flow rates during the first 4 h, compared to saline. The AUC0–4 h for saliva flow rate was significantly reduced by atropine (245 g vs 327 g) and the saliva phenytoin AUC0–4 h was significantly increased (5.6 μg · ml−1 · h vs 4.5 μg · ml−1 · h) without affecting plasma phenytoin concentrations. The saliva/plasma phenytoin AUC0–4 h ratio was therefore significantly increased by atropine (0.15 vs 0.12). However, there was a poor correlation between saliva/plasma phenytoin concentration ratios and saliva flow rates for the two treatments in the individual patients (correlation coefficient ranged from 0.25 to 0.65). These findings demonstrate that saliva phenytoin concentrations are increased by reductions in saliva flow rate. Caution is therefore required when saliva phenytoin concentrations are used for therapeutic monitoring in the presence of factors which may affect saliva flow rate.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00196118
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  • 95
    Electronic Resource
    Electronic Resource
    Conventional and controlled release diltiazem (1994)
    Springer
    European journal of clinical pharmacology 47 (1994), S. 75-79 
    Details
    ISSN: 1432-1041
    Keywords: Diltiazem ; Angina pectoris ; controlled release formulation ; metoprolol ; bioavailability ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Diltiazem CR tablets 120 mg b.i.d. for 1 week were compared with plain tablets 60 mg q.i.d. in 13 healthy male volunteers in a study of pharmcokinetic variables. Their antianginal efficacy was also compared in 23 patients with stable angina pectoris who were already on metoprolol. Both studies were of randomised, cross over design, and the clinical study was double blind. The pharmacokinetic variables of the two formulations were very similar except for the longer tmax of 4.4 h for diltiazem CR in comparison to 2.9 h for the plain tablets. The mean relative bioavailability of diltiazem CR in comparison with plain tablets was 1.14. The clinical study showed that after four weeks on diltiazem CR 120 mg b.i.d. or diltiazem plain tablets 60 mg q.i.d. in addition to metoprolol, there were significant decreases in weekly anginal attacks from 11 to 5 attacks/week, the number of nitroglycerin tablets consumed from 6 to 3 tablets/week, and an increase in the maximum workload from 116 to 126 and 123 W for diltiazem CR and plain diltiazem tablets, respectively, as compared to placebo. Five of the patients were angina free during diltiazem treatment. No difference in antianginal efficacy between the two preparations was seen. It was concluded that CR 120 mg b.i.d. appears bioequivalent to plain diltiazem tablets 60 mg q.i.d.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00193483
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  • 96
    Electronic Resource
    Electronic Resource
    Differences in the bioavailability of dihydrotachysterol preparations (1994)
    Springer
    European journal of clinical pharmacology 47 (1994), S. 81-84 
    Details
    ISSN: 1432-1041
    Keywords: Dihydrotachysterol ; bioavailability ; pharmacokinetics ; human ; HPLC
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract The bioavailability of four preparations containing dihydrotachysterol (DHT2) was tested in two separate trials with administration of single, oral doses of 1 mg per individual. The relative bioavailability of corresponding preparations (capsules vs capsules and oral solution vs oral solution) was tested in a randomised, crossover pattern within the same group of volunteers. Two different groups of 24 healthy volunteers took part in each trial. Solution and capsule bioavailability was also compared inter-individually. A new sensitive HPLC-method (quantification limit 0.5 ng · ml-1) was used for the measurement of DHT2 concentration in serum. Three of the preparations tested had a similar bioavailability (mean AUC values of 195.5–223 ng · h · ml-1); the bioavailability of the fourth preparation (A.T.10 oral solution) was considerably lower (mean AUC value 111.5 ng · h · ml-1). The present dosage recommendations of all four preparations are identical. A new dosage recommendation is thus required for the oral solution with low bioavailability (A.T.10).
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    URL: http://dx.doi.org/10.1007/BF00193484
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  • 97
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    Electronic Resource
    Pharmacokinetic analysis of sparse in vivo NMR spectroscopy data using relative parameters and the population approach (1994)
    Springer
    European journal of clinical pharmacology 47 (1994), S. 187-193 
    Details
    ISSN: 1432-1041
    Keywords: NMR spectroscopy in vivo ; drug tissue concentration ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract NMR spectroscopy in vivo when applied to studying drugs and their metabolites usually measures relative concentration in a tissue over time. Only ratios of clearance and volume parameters can be estimated from these data. Low drug dosages (relative to the sensitivity of in vivo NMR) or rapid drug elimination create the additional problem of data sparsity where a pharmacokinetic model cannot be fitted individually. We have investigated whether relative and absolute pharmacokinetic parameters can be estimated from such data by applying a population model. The data analysed were relative concentractions of 5-fluorouracil (FU) and of the sum of its catabolits α-fluoro-β-ureido-propanoic acid (FUPA) and α-fluoro-β-alanine (FBAL) in te liver, as monitored in 16 cancer patients by [19F]-NMP spectroscopy during and after a 10-min intravenous infusion of 650 mg FU·m−2. The “structural” part of the population model was a non-linear, two-compartment model featuring one FU compartment with volume V FU , a saturable clearance of FU by conversion into the catabolites where CL=v max /(k M +C FU ), a catabolite compartment with volume V cat , and a concentration-independent clearance of the catabolites, CL cat . The parameters actually fitted were: γ, v max , k M ·V FU , V cat /V FU , and CL cat /V cat where γ is a proportionality factor relating the NMR signal intensity of FU to the amount of FU in the body and, therefore, has no purely pharmacokinetic interpretation. All parameters were checked for random interindividual variation; γ and v max were also tested for inter-occasion variation. The program system NONMEM was used for model fitting. The estimated mean population parameters were: v max =121 μmol·min−1, k M ·V FU =2590 μmol, V cat /V FU =0.0648, CL cat /V cat =0.0555·min−1. The proportionality factor γ was found to depend on body weight and, in addition, to have an inter-occasion random variation (within patients, between examinations). No other random variation of a kinetic parameter could be identified. The estimated v max is similar to a reported estimate of 2.02 μmol·min−1·kg−1 derived from FU plasma kinetics. This study shows that sparse relative concentration data can be analysed by using relative parameters in a population model. Only one parameter has no unequivocal pharmacokinetic meaning due to the lack of absolute concentration information. Any contribution of the measuring procedure to the inter-occasion variation of in vivo NMP spectroscopy measurements should be minimized in order to allow the detection of possible inter-individual variances of the pharmacokinetic parameters.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00194971
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  • 98
    Electronic Resource
    Electronic Resource
    Distribution of a morphogenic peptide activating the head growth of hydra in rat organs following intravascular administration of3H-labeled peptide (1994)
    Springer
    Bulletin of experimental biology and medicine 118 (1994), S. 1162-1165 
    Details
    ISSN: 1573-8221
    Keywords: hydra head growth activator ; tissue and organ distribution ; pharmacokinetics ; metabolism
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract The organ distribution of radioactivity following intravascular bolus injection of3H-Lys-head growth activator in rats was studied. Two minutes after injection the renal level of radioactivity exceeded the blood level 7-fold; 80% of the total activity was bound with the blood cell membranes. An analysis of chemical derivatives of the labeled peptide in the plasma by means of reverse-phase high-performance liquid chromatography revealed the presence of several groups of radioactive metabolites with different hydrophilic properties. High-performance liquid chromatography of blood extracts obtained from samples taken 0.5, 1, 1.5, 2, 31, and 60 min after injection showed the transformation of initially hydrophobic head growth activator into more hydrophilic fragments. The3H-Lys-head growth activator-associated radioactivity could be reliably detected in the blood onl during the first two minutes after injection. The half-period of blood-to-organ distribution of3H-labeled head growth activator lasted less than 30 seconds.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02444613
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  • 99
    Electronic Resource
    Electronic Resource
    Comparative pharmacokinetics of fenbendazole in buffalo and cattle (1994)
    Springer
    Veterinary research communications 18 (1994), S. 209-216 
    Details
    ISSN: 1573-7446
    Keywords: absorption ; availability ; benzimidazole ; buffalo ; cattle ; fenbendazole ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Swamp buffalo (Bubalus bubalis) and Droughtmaster cattle (Bos indicus × B. taurus), fitted with gastrointestinal cannulae, were dosed intraruminally with fenbendazole at 7.5 mg/kg liveweight, together with a chromium oxide capsule and a pulse dose of NaCoEDTA, to estimate the flow dynamics of the digesta in the rumen and duodenum. The concentrations of fenbendazole (FBZ) metabolites were measured in plasma and duodenal fluid collected over 120 h. In plasma, significantly lower peak concentrations and earlier disappearance of FBZ and its sulphoxide (OFZ) metabolite were observed in buffalo, which considerably reduced systemic availability in comparison with cattle. The availability of OFZ in the duodenal fluid of buffalo was significantly lower, whereas FBZ disposition was similar to that in cattle. The turnover rate of fluid in the rumen was higher in buffalo than in cattle, while the flow parameters for other digesta were similar in the two species. It is concluded that the decreased absorption of drug in buffalo was attributable to the shorter residence time of the dose in the rumen, and probably in the entire gastrointestinal tract. This may reduce the efficacy of treatment and indicate the need for higher dose rates for benzimidazole anthelmintics in buffalo than in cattle.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01839270
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  • 100
    Electronic Resource
    Electronic Resource
    Pharmacokinetics and dosage regimen of cefotaxime in cross-bred calves following single intramuscular administration (1994)
    Springer
    Veterinary research communications 18 (1994), S. 313-318 
    Details
    ISSN: 1573-7446
    Keywords: calves ; cefotaxime ; cephalosporin ; dose ; intramuscular ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The pharmacokinetics, penetration into erythrocytes and plasma protein binding of cefotaxime were investigated in cross-bred calves. Following a single intramuscular dose of cefotaxime (10 mg/kg), the absorption half-life and elimination half-life were 0.13±0.03 h and 2.97±0.72 h, respectively. The apparent volume of distribution and total body clearance were 3.28±0.72 L/kg and 0.78±0.08 L/kg per h, respectively. The extent of penetration into erythrocytes was 24–40% of the total blood concentration. Cefotaxime was bound to plasma proteins of calves to the extent of 25.5–33.6%. A satisfactory intramuscular dosage regimen for cefotaxime in calves would be 11 mg/kg followed by 10 mg/kg at 7 h intervals.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01839199
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