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  • 1985-1989  (324)
  • 1986  (324)
  • Rat  (181)
  • pharmacokinetics  (143)
  • 1
    Electronic Resource
    Electronic Resource
    Springer
    Cellular and molecular life sciences 42 (1986), S. 169-171 
    ISSN: 1420-9071
    Keywords: Rat ; olfactory pathway selective lesions ; plasma corticosterone ; lactacidemia ; adrenal glands
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Summary In comparison to control rats, basal plasma corticosterone level and lactacidemia significantly increased in rats submitted to a bilateral lesion of the lateral olfactory tract and/or the anterior branch of the anterior commissure. Only the anterior branch of the anterior commissure induced hyperglycemia; that of the lateral olfactory tract exerted an opposite effect.
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  • 2
    Electronic Resource
    Electronic Resource
    Springer
    Anatomy and embryology 174 (1986), S. 123-144 
    ISSN: 1432-0568
    Keywords: Spinal cord ; Visceral afferents ; Somatic afferents ; Splanchnic nerve ; Dorsal column nuclei ; Sympathetic neurons ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The central projections of primary afferent fibers of the greater splanchnic nerve of the rat were investigated using the transganglionic horseradish peroxidase transport technique. In addition, the corresponding spinal ganglion cells and the preganglionic sympathetic neurons were demonstrated. For comparing visceral and somatic afferents, intercostal nerve afferents were labelled by the same technique. Splanchnic afferent dorsal root ganglion cells were found at segments T3 to T13 ipsilaterally, with the greatest density at T8 to T12. Labelled cells represented about 10%–15% of all neurons in the ganglia at maximal projection levels. They were randomly distributed within individual ganglia. The great majority were medium to small sized and round to slightly oval in shape. In the spinal cord, labelled visceral afferent axons were found maximally at T8 to T11, but could be detected in decreasing density up to T1 and down to L1. They were distributed over Lissauer's tract and the dorsal funiculus to a medial and lateral collateral pathway (MCP and LCP, respectively). The MCP, somewhat more prominent than the LCP, was destined primarily to clustered presumptive terminal fields in medial lamina I and outermost lamina IIa. Only a few axons continued further to laminae V and X. Splanchnic afferent axons, most likely derived from the MCP, formed a longitudinal bundle ventral to the central canal. The LCP consisted of more or less well-defined axon bundles emanating from the lateral Lissauer's tract and curving round the lateral edge of the dorsal horn and through the dorsolateral funiculus. Presumptive terminal sites of LCP axons are the lateral laminae I and IIa, the nucleus of the dorsolateral funiculus and the dorsal part of lamina V. A few LCP axons were seen in the vicinity of lateral dendrites of preganglionic sympathetic axons. Visceroafferent terminals were absent from laminae IIb–IV and VII. The possible consequences of the MCP/LCP duality for the central connections of splanchnic afferents are discussed. Some splanchnic afferents ascended to the gracile and cuneate nuclei, and rarely to the spinal trigeminal nucleus. These results fit into the general concept of visceroafferent terminal organization that has emerged during the last few years. Differences to other reports in the detailed arrangement of fibers and terminals are discussed. Somatoafferent cell bodies represented the vast majority of neurons in the respective spinal ganglia. Cell sizes encompassed the whole range from very small to very large without a clear predominance of one particular size class. Cell shapes of somatic neurons were more variable than those of visceral afferent neurons. Somatic afferent fibers and presumptive terminals in the spinal cord are distributed ipsilaterally to dorsal horn laminae I–V, most heavily II–IV, to the nucleus dorsalis Clarke, to the ventral horn, and also sparsely to the dorsal horn contralaterally. Labelled preganglionic sympathetic neurons were found in segments T3–T13. The vast majority was located in the intermediolateral nucleus. Fewer neurons occurred in the intercalated nucleus, and occasionally a neuron was labelled in the dorsal grey commissure.
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  • 3
    ISSN: 1432-0568
    Keywords: Dorsal lateral geniculate nucleus ; Glial cell number ; Neuron number ; Postnatal development ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Quantitative changes in cell number during development of the dorsal lateral geniculate nucleus were determined using semithin serial sections of tissue obtained from 28 rats on postnatal day 0, 5, 8, 10, 20, 30, 90 or 165. Our results show three phases of postnatal development in the rat dorsal lateral geniculate nucleus: phase 1 from birth until eye opening, which occurs around the 12th day in these litters; phase 2 from eye opening through stabilization of neuron number on the 30th postnatal day, and phase 3 from that event until adulthood. During the first period increases in neuron number and in glial cell number are found accompanying a nearly seven-fold increase in dorsal lateral geniculate nucleus volume. Phase 2 includes a high incidence of neuronal cell death and a continuous increase in the number of glial cells. The third phase is characterized by a stabilization in the number of neurons, although the glial cell number continues to increase. Neuronal density decreases exponentially throughout the postnatal life of the rat, while the density of glial cells remains relatively stable over the period of study. The postnatal phenomenon of an initial increase in neuron number followed by a period of neuron death may be related to modulating and plastic functions which occur in the rat dorsal lateral geniculate nucleus before a stable neuronal population is achieved on the 30th postnatal day.
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  • 4
    Electronic Resource
    Electronic Resource
    Springer
    Anatomy and embryology 173 (1986), S. 401-411 
    ISSN: 1432-0568
    Keywords: Claustrum ; Subcortical connections ; Fluorescent tracers ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The retrograde fluorescent tracers Fast Blue (FB) and Diamidino Yellow (DY) have been used to study subcortical afferents of the claustrum. DY or FB was injected into the claustrum. The greatest amount of labeled cell bodies were observed in the posterior thalamic nuclear complex. They were especially abundant in its caudal part, lying between the medial geniculate body and the pretectal area. In comparison to the numerous labeled cells near the diencephalic-mesencephalic junction, the number of fluorescing neurons in the brain stem was considerably lower. These neurons were mostly concentrated in the monoaminergic cell groups. The results indicate the presence of a substantial projection from the posterior thalamic and anterior pretectal region to the calustrum.
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  • 5
    Electronic Resource
    Electronic Resource
    Springer
    Anatomy and embryology 173 (1986), S. 377-383 
    ISSN: 1432-0568
    Keywords: Rat ; Muscle ; Myotendinous junction ; Acetylcholinesterase ; Reinnervation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The non-endplate (sarcoplasmic) acetylcholinesterase (AChE) was investigated in eight different muscles of the rat. Serial consecutive sections were stained for AChE, myofibrillar ATPase (after alkaline and acid preincubation), and cytochrome C-oxidase. The following general correlation could be established: within a given muscle the sarcoplasmic AChE was highest in type IIB fibers, lowest in type I and intermediate in type IIA. Additionally, the intensity of the reaction was directly proportional to the size of the type IIA fibers. The distribution of sarcoplasmic AChE was correlated to the ATPase fiber types but was complementary to the cytochrome C-oxidase staining pattern. In single fiber preparations, accumulation of AChE at the myotendinous junction was found to occur in “caplike” form exclusively in fibers with very low or absent sarcoplasmic AChE. To study the role of innervation in the expression of the sarcoplasmic AChE, we cross-reinnervated the extensor digitorum longus (EDL) muscle with the soleus (SOL) nerve and vice versa (X-EDL, X-SOL). In the X-EDL the sarcoplasmic AChE was transformed to that of a normal SOL as were also the ATPase and the cytochrome oxidase. Surprisingly, in the X-SOL the high AChE activity typical for a normal EDL was present after 3 weeks but decreased steadily to very low levels lacking any correlation with ATPase and cytochrome oxidase. The results suggest that the cytoplasmic AChE of the SOL muscle depends more on the load-bearing function of the muscle than on the imposed impulse pattern. There is additional evidence for a retrograde effect of the X-SOL upon its motoneurons.
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  • 6
    Electronic Resource
    Electronic Resource
    Springer
    Anatomy and embryology 173 (1986), S. 385-391 
    ISSN: 1432-0568
    Keywords: Elastic cartilage ; Chondrogenesis ; External ear ; Rat ; Ultrastructure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Selected ultrastructural features of chondrocytes and the extracellular matrix in the developing elastic cartilage of the external ear were studied in rat fetuses and young animals. The cytoplasmic lipid droplets were first observed in the 19-day fetus. They increase in number and size during the first post-natal week. The elastogenesis proceeds in the sequence: oxytalan fibers (17-day fetus), elaunin fibers (1-day rat), elastic fibers (5-day rat). Intermediary stages between the randomly oriented individual microfibrils and bundles of microfibrils (oxytalan fibers) were also observed.
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  • 7
    Electronic Resource
    Electronic Resource
    Springer
    Anatomy and embryology 173 (1986), S. 371-376 
    ISSN: 1432-0568
    Keywords: Motilin-like immunoreactivity ; RIA ; HPLC ; Cat ; Intestine ; Rat ; Cerebellum ; Purkinje cells ; Dendrites ; Neocortex ; Pyramidal cells ; Hippocampus
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Motilin was demonstrated by the immunoperoxidase technique in endocrine cells of the gastrointestinal tract using several specific antisera. Motilin-like immunoreactivity could only be demonstrated with one of these antisera and was observed in Purkinje cells and dendrites of the cerebellum, in pyramidal cells and dendrites of the cerebral cortex and in dendrites of the CA3 field of the hippocampus of the rat. Very low motilin-like immunoreactivity was found in cerebellum as well as in cerebral cortex using radioimmunoassay. However, using reverse phase liquid chromatography combined with UV-detection and radioimmunoassay, no peak of a peptide corresponding to synthetic motilin was detectable in rat cerebellar extracts, in contrast to findings in rat duodenum. The results do not suggest that motilin is an intrinsic neuroactive substance of the cerebellum.
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  • 8
    Electronic Resource
    Electronic Resource
    Springer
    Anatomy and embryology 175 (1986), S. 147-150 
    ISSN: 1432-0568
    Keywords: Heart separation ; Aorta ; Pulmonary trunk ; Heart development ; Chicken ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary A comparative study was made of the relative position of the outflow tracts of chicken and rat hearts with respect to the ventricles during septation. For this purpose the position of the left and right ventricular outlet including the aortic and pulmonary valve primordia and the left and right ventricle were established with respect to the midsagittal plane of the embryo, using reconstructions of serial sections of chicken (stage 28–30) and rat (stage 28–30) embryos. In the chicken embryo no rotation of the outflow tract occurs, i.e. the position of the aortic and pulmonary valve primordia with respect to the left and right ventricle remains the same. In the rat embryo a clockwise rotation of the aortic and pulmonary valve primordia with respect to the ventricles does occur. This is in fact a detorsion. The left and right ventricle and the left ventricular outlet do not show change in position with regard to the midsagittal plane. The left ventricular outlet always straddles the interventricular septum, both lying in the midsagittal plane. These interspecies differences in the degree of detorsion of the outflow channels before septation may explain the differences in the extent of the region of contact between the endocardial outflow tract ridges.
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  • 9
    Electronic Resource
    Electronic Resource
    Springer
    Anatomy and embryology 175 (1986), S. 189-198 
    ISSN: 1432-0568
    Keywords: Capillaries ; Tooth pulp ; Odontoblasts ; Mineralisation ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Although the rat incisor is used widely in the study of dentinogenesis there is little information on the pulp capillaries and the fate of the pulp contents incisally. The capillaries have now been described in relation to the life cycle of the odontoblasts using light microscopy on perfusion fixed teeth and SEM on pulp vascular casts. Odontoblast precursors differentiated to preodontoblasts in the absence of local vessels. Capillaries entered the zone subjacent to preodontoblasts prior to their transformation to odontoblasts. They invaded the odontoblast layer after formation of odontoblast processes and during lengthening of their cell bodies. These capillaries formed a dense plexus which was separated from the predentine by about 10 μm thickness of odontoblast cytoplasm. Electron microscopy near the incisal end showed that the odontoblasts lost their processes and their polarity to form postodontoblasts. This coincided with the deposition of atubular collagenous tissue at the periphery of the pulp. Loss of fenestrations in the capillaries seemed to coincide with the diminution of odoncoblast function. Odontoblastic capillaries were lost before the postodontoblasts became separated from one another. There was evidence of degenerating vessels, cells and extracellular debris near the incisal end. Light and transmission electron microscopical evidence from demineralised teeth was correlated with SEM evidence from anorganically prepared specimens and considered in relation to dynamic events at the incisal surface. Thus the pulp closure region was found to include a central zone of mineralised, moribund pulp cells and debris surrounded by atubular tissue.
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  • 10
    Electronic Resource
    Electronic Resource
    Springer
    Anatomy and embryology 174 (1986), S. 407-411 
    ISSN: 1432-0568
    Keywords: Undulating course of nerve fibre ; Endoneural collagen ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The undulating course of nerve fibres and the optical effect of that course, i.e. the bands of Fontana, were studied in the peripheral nerves of the adult rat using light microscopy. The arrangement of collagen fibres in the endoneurium of these nerves was evaluated using transmission and scanning electron microscopy. No nerve fibres undulation was noted on the intracranial sections of the cranial nerves or on the spinal roots. In their endoneurium a few, irregularly arranged collagen fibrils were found. In contrast, the nerve fibres undulation and Fontana's bands were a constant feature in the peripheral course of the nerve trunks. They were discernible in vivo and on excised unfixed as well as fixed nerves. The nerve fibres follow a sine-curve course of variable frequence and amplitude. Exposed in vivo, the nerve fibres retained their wave-like course even after removal of the epineurium and perineurium. The endoneurium of these nerves contained numerous undulating longitudinally oriented bundles of collagen fibrils. These findings suggest that the undulating course of the nerve fibres in peripheral nerves is conditional upon the quantity and arrangement of their endoneurial collagen fibrils. When the nerve was stretched in the course of movement, the undulation became straightened out until it disappeared. Conversely, nerve shortening enhanced the undulation. Thus the wave-like alignment of the nerve fibres represents a physiological reserve length for nerve stretching.
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  • 11
    Electronic Resource
    Electronic Resource
    Springer
    Acta neuropathologica 71 (1986), S. 55-63 
    ISSN: 1432-0533
    Keywords: Axon reaction ; Chromatolysis ; Axotomy ; Acrylamide ; Spinal ganglia ; Sensory neurons ; Neurofilaments ; Mitochondria ; Intoxication ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Rats were given acrylamide in doses of either 30 or 50 mg/kg (5 days each week) for up to 3 weeks and killed at weekly intervals. The right sciatic nerve was tied tightly at the level of the major trochanter 4 days before killing the animals by perfusion fixation when ipsilateral and contralateral sensory ganglia (L5 and L6) were removed. The effects on neuronal perikarya of axotomy alone, of acrylamide alone and of these combined were studied by light and electron microscopy. The responses to axotomy and to acrylamide intoxication shared certain features, namely peripheral Nissl substance and to a lesser degree nuclear eccentricity, nucleolemmal crenation and mitochrondrial enlargement. Neurofilament loss was present only with acrylamide. In combined axotomy and acrylamide all these five features were prominent. These findings indicate firstly that the individual reponses to axotomy and to acrylamide, while sharing several features, are subtly different and secondly that acrylamide appears to impede the vital neuronal responses directed towards repair of the axon.
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  • 12
    ISSN: 1432-0738
    Keywords: Ethanol ; Lead ; Ischaemia ; Induced arrhythmias ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The aim of this study was to investigate whether chronic (3 or 10 months) administration, via the dinking water, of lead (25 ppm) and/or ethanol (25% v/v) altered the susceptibility of the heart to arrhythmias induced either by coronary artery occlusion or noradrenaline infusion in pentobarbitone-anaesthetised male Sprague-Dawley rats. The cardiac effects of acute intravenous infusions of ethanol (17, 33 and 66 mg kg−1 min−1) were also measured. Chronic exposure to ethanol and/or lead in the drinking water had no marked effect on the severity of arrhythmias occurring within the initial 30 min of coronary artery occlusion. In control rats and in those administered ethanol and/or lead for 10 months, noradrenaline (16 μg kg−1 min−1 given IV 1 h post-occlusion for a 15-min period) induced a similar number of ectopic beats during the infusion period, although these arrhythmias persisted beyond the infusion period in treated animals only. There was a significant accummulation of lead in the bone but not in the blood of lead-treated rats. Blood ethanol concentrations varied considerably between animals, ranging from 0 to 319 mg%. Ethanol (66 mg kg−1 min−1) given acutely and yielding a blood concentration of 174 mg % had a slight antiarrhythmic effect in this model.
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  • 13
    ISSN: 1432-0738
    Keywords: Dibutylnitrosamine ; Metabolism ; Human ; Rat ; Liver ; intestine
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The metabolism of the bladder carcinogen N-nitroso-di-n-butylamine (NDBA) was studied in microsomal preparations of tissues of patients of both sexes, aged 59–69 years undergoing abdominal surgery. Samples of liver, ileum, and colon were of normal histological appearance. For comparison, samples of rat liver and small intestinal mucosa microsomes were included in the study. Using 1-14C-labeled NDBA, the biotransformation to hydroxylation products retaining the nitroso group, NDBA-2-OH, NDBA-3-OH, and NDBA-4-OH, respectively, was investigated by reversed phase HPLC. In order to separate these metabolites, pooled samples were analysed by normal phase HPLC. The rate of hydroxylation of NDBA was found to be 5.5 times higher in rat liver microsomes compared to those from human liver (2.86±0.29 vs 0.52±0.03 nM x min−1 x mg−1). NDBA-3-OH proved to be the major metabolite formed (〉80% of total metabolites). The metabolism of NDBA was low but detectable in seven out of nine specimens of human gut, 0.1–0.5 nM x mg−1 in 1 h of incubation, and of the same order of magnitude in rat intestinal tissue (0.4–0.6 nM x mg−1).
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  • 14
    ISSN: 1432-0738
    Keywords: Smoke ; Titanium tetrachloride ; Zinc chloride ; Hexachloroethane ; Inhalation toxicity ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Rats were exposed to white smoke generated from mixtures of titanium dioxide-hexachloroethane (TiO2-HC) and zinc-hexachloroethane (Zn-HC), respectively, in an inhalation chamber operated in the static mode. The dose was varied by varying the amount of smoke mixture and/or the exposure time. The acute inhalation toxicity of TiO2-HC smoke was much lower than the Zn-HC smoke. Thus, the animals survived exposure to TiO2-HC smoke, even at relatively high smoke concentrations. This smoke was irritating to the animals and minor, acute inflammatory changes were seen in lung tissue. In contrast, Zn-HC smoke was very toxic and caused lethal injuries to the experimental animals, even at relatively low concentrations. Pulmonary injuries were extensive and death was due to blood congestion with pulmonary oedema. Since the TiO2-HC and Zn-HC mixtures form TiCl4 and ZnCl2, respectively, a separate study was performed in which rats were exposed to TiCl4 gas or ZnCl2 aerosol. No animals died from exposure to TiCl4 at concentrations between 370 and 2900 mg/m3 for 10 min. The LC50 of ZnCl2 was found to be around 2000 mg/m3 during a 10-min exposure period. The difference between the two types of smoke is explained by the difference in toxicity between TiCl4 and ZnCl2.
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  • 15
    Electronic Resource
    Electronic Resource
    Springer
    Archives of toxicology 59 (1986), S. 279-284 
    ISSN: 1432-0738
    Keywords: Immunotoxicity ; Immunosuppression ; Immune response ; Humoral immune response ; Cell-mediated immune response ; Endosulfan ; Pesticide ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The present study was designed to evaluate the effect of sub-chronic doses of endosulfan on humoral and cell-mediated immune (CMI) responses in albino rats. Male albino rats were given a diet containing 5, 10 or 20 ppm endosulfan for 8–22 weeks and immunized with tetanus toxoid in Freund's complete adjuvant subcutaneously 20 days before terminating the exposure. The humoral immune response was studied by serum globulin level, immunoglobulin (IgM and IgG) concentration and antibody titre against tetanus toxoid. The CMI response was studied by leucocyte migration inhibition (LMI) and macrophage migration inhibition (MMI) factors. The antigen-induced increases in serum globulin fraction and immunoglobulin level were reduced at high doses of the endosulfan after 12 weeks of exposure. Antibody titre was significantly decreased in endosulfan-exposed rats at 10 and 20 ppm levels and a consistent trend was observed. Rats in the 10 and 20 ppm dose groups had significantly depressed LMI and MMI responses. Results obtained in this study revealed marked suppression of the humoral and CMI responses in rats administered with sub-chronic doses of endosulfan. Both cellular and humoral immune responses were decreased in a dose-time dependent pattern. Suppression of immune responses by endosulfan is clearly an important aspect of its toxicology.
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  • 16
    Electronic Resource
    Electronic Resource
    Springer
    Experimental brain research 62 (1986), S. 203-206 
    ISSN: 1432-1106
    Keywords: GABAergic terminals ; Visual cortex ; Rat ; Monocular enucleation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Rats that had one eye removed on the day of birth were examined at various postnatal ages with immunocytochemical methods to determine the effect on the development of the GABAergic axonal plexus in the visual cortex. The monocular segment of visual cortex contralateral to the enucleated orbit had 20–30% fewer GABAergic axon terminals than the monocular segment of visual cortex contralateral to the normal eye. Other cortical areas did not show any significant changes. These findings suggest that sensory deprivation of the visual cortex interferes with the normal development of GABAergic neurons.
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  • 17
    ISSN: 1432-1106
    Keywords: Rat ; Dorsal lateral geniculate nucleus (dLGN) ; Interneurons ; Golgi/EM ; GABA immunocytochemistry
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Identified neurons in the dorsal lateral geniculate nucleus (dLGN) of the rat were studied using a Golgi/EM procedure in combination with post-embedding GABA immunocytochemistry. The results of this investigation identify clearly the GABA-immunoreactive nature of the two morphologically] distinct neuronal populations found within the rat dLGN — thalamocortical relay cells are GABA-immunonegative whilst the putative ‘interneurons’ are GABA-immunopositive. This immunocytochemical evidence strongly suggests that ‘interneurons’ synthesize and use GABA to mediate their local inhibitory synaptic mechanisms within the dLGN of the rat.
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  • 18
    Electronic Resource
    Electronic Resource
    Springer
    Experimental brain research 64 (1986), S. 19-26 
    ISSN: 1432-1106
    Keywords: Cholinergic innervation ; Brain stem ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Efferent vestibular and cochlear neurons were identified in the rat's brain stem by retrograde labelling with True Blue (TB) or wheat germ agglutinin — horseradish peroxidase (WGA-HRP) injected into the utricle. Such cells were found at the same locations described in 1983 by White and Warr (ipsilateral superior olivary nucleus (LSO), bilateral latero-ventral nucleus of the trapezoid body (LTz) bilateral group E medial and lateral to the genu facialis) and, in addition, bilaterally in the caudal pontine reticular nucleus (CPR) at the level of the descending facial nerve. Cholinergic neurons were identified by counterstaining sections containing TB filled perikarya for (1) acetylcholinesterase (AChE) following pretreatment with diisopropylfluorophosphate (DFP) or (2) choline acetyltransferase (ChAT), by immunohistochemistry with highly specific monoclonal antibodies. Many, but not all, vestibular efferent cell bodies located in group E were shown to be cholinergic. These and other recently published data suggest that the efferent octavus system may consist of a number of chemically distinct cell groups.
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  • 19
    ISSN: 1432-1106
    Keywords: Visual deprivation ; Rat ; Visual cortex ; Neurons ; Glia ; Stereology
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The effects of dark-rearing and light-exposure on the distribution of neurons and glial cells types in the rat visual cortex (area 17) have been investigated. Three groups of animals were studied: i) rats reared in the dark until weaning at 21 days post natum (21 DPN) and subsequently light-exposed for 31 days (Group 21/31); ii) rats darkreared until 52 DPN and then exposed to light for 3 days (Group 3 dL); and iii) rats totally dark-reared until 52 DPN (Group 52 dD). Semithin sections tangential to the pial surface were obtained at sampling intervals 50 μm apart throughout the depth of the left visual cortex. The volume numerical densities of neurons, astroglia, oligodendroglia, and microglia, at each sampling strata in the cortex were calculated using stereological techniques. The laminer density and distribution of neurons was not significantly different between the three groups. In comparison with group 21/31 there was a marked reduction in the densities of astroglia, oligodendroglia, and microglia in lower layer 5 of groups 3 dL and 52 dD. Additionally, the density of microglia in thalamorecipeint layer 4 was greatly increased in group 3 dL compared with groups 21/31 and 52 dD. These results indicate specific alterations in the glial cell composition of the rat visual cortex following periods of dark-rearing and light-exposure. Furthermore, changes in the density of glial cells in layer 5 may reflect functional modifications in neurons projecting to the superior colliculus.
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  • 20
    ISSN: 1432-1106
    Keywords: Cerebellum ; Pedunculotomy ; Autoradiography ; Retrograde fluorescence ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary A left cerebellar pedunculotomy was carried out in neonatal rats of different ages to deprive the left cerebellar hemisphere of its normal climbing fibre input. In control adult animals this is totally crossed and thus arises only from the contralateral (right) inferior olive. After pedunculotomy, only the left inferior olive was intact, the right being degenerated. The remaining olivocerebellar pathway was investigated using anterograde autoradiographic or retrograde fluorescent double-labelling techniques. The anterograde autoradiographic technique showed that, in these animals, the remaining left inferior olive had an aberrant climbing fibre projection which travelled via the intact right inferior cerebellar peduncle to the denervated left hemicerebellum. If the pedunculotomy was carried out at 3 days of age (P3), this aberrant projection closely mirrored the normal pathway to the opposite hemisphere; pedunculotomy at P7 produced a different pattern of projection; while if the operation was done at P10 there was no new projection. True blue (TB) and diamidino yellow (DY) were injected into the denervated (left) and normal (right) cerebellar hemispheres respectively. Retrograde transport of these tracers confirmed both the aberrant ipsilateral projection and the normal crossed projection from neurons in the remaining inferior olive. Most of the ipsilaterally projecting neurons were in the medial accessory olive. As none of them were double-labelled, it was concluded that the new projection is not a collateral of normally projecting olivary neurons, but arises from a separate population of cells. The significance of these findings in relation to earlier work on this system is discussed.
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  • 21
    ISSN: 1432-1106
    Keywords: Corticotropic system ; Corticotropin releasing hormone ; Vasopressin ; Colchicine ; Neuronal functional state ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The specific immunoreactivity of neurons containing corticotropin-releasing hormone (CRH) or vasopressin (Vp) was studied both centrally, in the parvocellular division of the paraventricular nucleus, and distally, in the external median eminence. Control rats were compared with adrenalectomized rats and with animals supplemented with corticosterone or dexamethasone, either without additional treatment, or 24, and 48 h after an intraventricular injection of colchicine. In all groups of animals, colchicine induced a progressive and parallel decrease in both CRH and Vp immunoreactivity within the axons of the external median eminence. A semi-quantitative estimation of this axonal immunostaining showed that the decrease was clearly correlated with the axons' releasing activity according to the different functional states of the adrenocorticotropic system. Increased rates of hormonal release induced by adrenalectomy could be seen in the accelerated depletion of axonal immunoreactivity whereas corticosteroid supplementation had the opposite effect. Correspondingly, the progressive intensification of the CRH and Vp immunoreactivity within the perikarya following colchicine treatment was further markedly enhanced in adrenalectomized rats and diminished after corticosteroid supplementation. Taken together, these data suggest that in these neurons, perikaryal hormone synthesis may be closely related to the releasing activity of the axon terminals. They further point to appropriate colchicine treatment as useful tool for evaluating the functional state of CRH and Vp neurons of the parvocellular paraventricular nucleus under various experimental conditions.
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  • 22
    ISSN: 1432-1106
    Keywords: Cerebral cortex ; Rat ; Evoked potentials ; Cerebral veins
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Visual and somatosensory evoked potentials were mapped in the cerebral cortex of adult rats and, after filling the cerebral arteries and veins with dye, the mappings were then compared to the distribution of pial veins. A close relationship was found between the position, size and shape of the occipital venous drainage field and the distribution of visual evoked potentials with high amplitudes and short latencies. Accordingly, such potentials evoked by stimulation of the forepaw and the tailroot were confined to the fronto-parietal drainage field. In the case of individual variations in the expansion and shape of sensory areas, the medial and lateral borders of the occipital drainage field and the medial border of the fronto-parietal drainage field covaried. Only at the common border between these two drainage fields, visual evoked potentials with small amplitudes and long latencies extended into the parietal drainage field and overlapped with somatosensory evoked potentials. This overlapping area corresponds in position to the anterior part of the peristriate cortex. A comparison between the vascular organization and cytoarchitectonic maps of the rat cortex indicates that other parts of the characteristic pattern of venous drainage fields may also correlate with the cytoarchitectonic and functional organization of the cerebral cortex. These observations suggest that during morphogenesis the formation of sensory projections to the cerebral cortex may interact with the angiogenesis, mainly with the development of veins.
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  • 23
    ISSN: 1432-1106
    Keywords: TRH-neurons ; Immunoelectron microscopy ; Synapse ; Hypothalamus ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Immunoreactive TRH-containing neurons and their synaptic associations were studied electron microscopically in the paraventricular nucleus (PVN) and dorsomedial nucleus (DMH) of the rat hypothalamus. In propylthiouracil (PTU)-treated rats, the immunoreactive cell bodies in the PVN appeared to be activated, showing a hypertrophic perikaryon, well developed Golgi bodies and numerous secretory granules. No such alterations were evident in the TRH neurons in the DMH. These findings suggest that the PVN-TRH neurons are involved in the hypothalamic-hypophysial-thyroid axis. Further, it was shown that unlabeled nerve terminals containing small and large clear vesicles make synaptic contacts with the TRH perikarya in the PVN. Thus it is likely that PVN-TRH neurons are regulated both by thyroid hormones and by other neuronal signals. In the DMH, unlabeled nerve terminals containing small and large clear vesicles, and immunoreactive terminals form synapses with TRH neurons. Thus the DMH-TRH neurons may be under dual neuronal control. It was further noted that in the DMH and PVN, TRH nerve terminals make synaptic contacts with other unlabeled neurons. It is evident that TRH acts as a neurotransmitter or neuromodulator, although the origin of TRH terminals should be elucidated.
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  • 24
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    Experimental brain research 62 (1986), S. 549-559 
    ISSN: 1432-1106
    Keywords: Cutaneous receptive fields ; Somatosensory cortex ; Cortical layers ; Quantitative analysis of receptive fields ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Quantitative techniques were used to demonstrate cortical layer differences in cutaneous receptive fields (RF's) in the rat SI cortex. Two- and three-dimensional (2-D and 3-D) RF maps were constructed showing the responsiveness of single neurons to standardized punctate stimulation of each of a matrix of points on the skin or the mystacial vibrissa pad. These allowed a visualization not only of the overall sizes of such RF's, but also their shape and “response profile”. Initial experiments showed that the sizes and response profiles of such RF's were similar whether they were mapped by sinusoidal mechanical vibration of skin, punctate touch, or direct intracutaneous electrical stimulation. This method was used to quantitatively determine distoproximal lengths of RF's of single units recorded at different depths in the forepaw area of the SI cortex. Plots of these RF lengths as a function of cortical depth showed that the smallest RF's were found in the granular layers (IV and deep III). RF's up to double that size were found in supragranular layers, and up to triple that size in infragranular layers. 3-D maps of RF's in the granular layers showed sharp central response peaks surrounded by very steep dropoffs to the RF boundaries. In the whisker areas, granular layer RF's were typically circular in shape and contained from 1–4 whiskers. By contrast, in supragranular layers they were often elongated in shape, and were oriented along rows or columns of whiskers. RF's in layer V resembled large, high plateaus, often supporting clearly separated peaks. RF's mapped in the fore- and hindpaw areas were similar, but, even in the granular layers, were often slightly elongated along the limb axis. In all regions of the SI, both the locations and shapes of the granular layer RF's appeared to be conserved as subsets of other more topographically heterogeneous RF's encountered elsewhere in the column. These findings may correlate with patterns of axonal connectivity in the rat SI.
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  • 25
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    Experimental brain research 62 (1986), S. 572-578 
    ISSN: 1432-1106
    Keywords: Vasopressin cell ; Noxious input ; Hypovolemia ; Supraoptic nucleus ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The effects of saphenous nerve stimulation on discharge activity of supraoptic neurosecretory (NS) cells were studied in anesthetized rats. Of 112 supraoptic neurosecretory cells, 62 exhibited a ‘phasic’ discharge pattern. The nerve stimulation transiently excited 46 of these 62 ‘phasic’ units, as well as 35 of the 50 remaining ‘non-phasic’ units. No appreciable blood pressure change was noted using PSTHs with 1-ms resolution. Though the nerve stimulation also evoked a flexor reflex of the ipsilateral hind limb, blockage of the hind limb movement with gallamine did not alter the amplitude of the supraoptic cell excitation. The threshold of the nerve stimulation was higher for the excitation than for the flexor reflex. Effects of hypovolemic and hyperosmotic stimuli on discharge activity of ‘phasic’ cells during saphenous nerve stimulation were studied to find a possible interaction between these stimuli. Hemorrhage potentiated the transient excitation evoked by the nerve stimulation in all of the 8 ‘phasic’ cells tested, while no such effect was seen after an injection of hypertonic sodium chloride solution in the 7 ‘phasic’ cells tested. These electrophysiological data suggest that hypovolemic and noxious stimuli potentiate VP secretion in a synergistic manner but that hyperosmotic and noxious stimuli do not.
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  • 26
    ISSN: 1432-1106
    Keywords: Rat ; Voltammetry ; High performance liquid chromatography (HPLC) ; 5-hydroxyindolacetic acid (5-HIAA) ; Uric acid (UA)
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Differential pulse voltammetry was performed in rats chronically implanted with carbon fiber electrodes in the caudate (n.Cd) and raphe dorsalis (n.RD) nuclei. The electrochemical signal obtained at the +300 mV potential (peak 3) in animals implanted for more than one week (long term chronic conditions, 〉7 days) could be dependent upon the extracellular fraction of 5-hydroxyindolacetic acid (5-HIAA) since a single injection of Pargyline is sufficient to suppress it in n.Cd and n.RD. This result was obtained despite the tendency of Pargyline to increase n.Cd and n.RD endogenous concentrations of Uric Acid (UA) measured by High Performance Liquid Chromatography (HPLC). In contrast, in animals implanted for less than one week (short term chronic conditions, 〈7 days) peak 3 recorded in the same structure could be dependent upon extracellular fractions of 5-HIAA and UA since consecutive injections of Pargyline and Allopurinol are necessary to suppress this signal. The source of extracellular UA measured in brain by voltammetry, in such short term chronic conditions, might result from surgical trauma.
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  • 27
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    European journal of clinical pharmacology 30 (1986), S. 615-617 
    ISSN: 1432-1041
    Keywords: fluocortolone ; pharmacokinetics ; protein binding ; synthetic corticoid ; clearance ; volume of distribution
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The kinetics of the synthetic corticoid fluocortolone was determined in 9 healthy female volunteers after a single oral dose of 20 mg. The maximal plasma level fluocortolone (Cmax) of 202±70 ng/ml occurred within 85±32 min of oral intake after which it declined monoexponentially. Total plasma clearance was 6.48±2.07 ml/min·kg and the clearance of unbound fluocortolone was 60.38±26.67 ml/min·kg. Plasma protein binding was 83 to 95%. The volume of distribution at steady-state was 1.01±0.34 l/kg for total fluocortolone and 11.21±3.77 l/kg for unbound drug. The results of the study characterize the kinetics of unbound fluocortolone for the first time. In addition, the kinetics of total fluocortolone presented here confirm values calculated previously.
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  • 28
    ISSN: 1432-1041
    Keywords: propafenone ; antiarrhythmic drug ; therapeutic range ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In 11 patients with stable premature ventricular beats, the kinetics of single (150 and 300 mg) and multiple (150 mg t.i.d. and 300 mg t.i.d.) oral doses of propafenone were studied with reference to arrhythmia suppression. During the acute phase detectable plasma levels of the drug were achieved only with the higher dose. In 8 out of 10 patients the antiarrhythmic effect was obtained with the 300 mg dose, which was found to predict responsiveness at steady-state. During the chronic phase, antiarrhythmic efficacy was obtained with the lower dose regimen (150 mg t.i.d.) in half of those patients. A wide range of effective plasma levels was observed. The previously suggested therapeutic range (0.5–2.0 µg/ml) was not adequate in predicting either antiarrhythmic activity or adverse effects. The results show the role of propafenone metabolites in determining total antiarrhythmic action.
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  • 29
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    European journal of clinical pharmacology 31 (1986), S. 15-22 
    ISSN: 1432-1041
    Keywords: pirmenol ; ventricular arrhythmias ; antiarrhythmic drug ; initial- and long-term experience ; pharmacokinetics ; adverse effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Pirmenol, a new class IA antiarrhythmic agent, has shown promise in short-term trials, but long-term efficacy has not been documented. We thus evaluated 11 patients with frequent (≥60/h) premature ventricular complexes (PVC) given oral pirmenol for 25–727 days. Ten of 11 patients entering the long-term open trial had shown ≥70% (mean 83%) PVC suppression during in-hospital pirmenol dose ranging. Long-term pirmenol was given in divided doses of 100–600 mg/day. Mean PVC frequency during baseline was 13,078/24h (range, 3,218–32,718); couplets averaged 481/24h (1–2,829) and runs 45/24h (0–334). Ambulatory monitoring was performed at 1, 3, 6, and 12 months, then semiannually. Mean absolute PVC suppression at 1 month averaged 75% (p≤0.02). Median individual percentage PVC suppression was 94%. During the first 3 months, 8 patients (73%) continued to show a favorable response (≥70% suppression), and 3 had arrhythmia recurrence and were dropped. One responder was withdrawn after the onset of paroxysmal atrial fibrillation, and another early responder was withdrawn after 3 months because of arrhythmia relapse. Six patients have been treated for over 1 year, with 99% mean PVC suppression. Mean couplet and run frequencies at 1 month decreased by means of 76% (p≤0.05) and 92% (p=0.001) respectively. At 1 year, couplets were suppressed 99.8% and runs by 99.7% in the 6 patients remaining on pirmenol. Mean QT interval increased slightly (7.1%,p〈0.05); mean PR and QRS intervals were unchanged. Plasma pirmenol concentrations averaged 1.49 µg/ml at clinic evaluations, 1.72 µg/ml in responders vs 1.08 µg/ml in nonresponders. Inade-quate plasma drug concentrations may be one cause for arrhythmia recurrence. Adverse effects were minimal. Thus, oral pirmenol is a safe and effective agent for long-term outpatient management of complex ventricular arrhythmias in selected patients.
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  • 30
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    European journal of clinical pharmacology 31 (1986), S. 69-72 
    ISSN: 1432-1041
    Keywords: quinidine ; sparteine ; pharmacokinetics ; drug oxidation ; polymorphism
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics and metabolism of quinidine were investigated in extensive and poor metabolisers of sparteine. No differences in plasma clearance, terminal half life, volume of distribution or cumulative urinary excretion of quinidine, 3-hydroxyquinidine and quinidine-N-oxide were observed between phenotypes. Thus, it is unlikely that quinidine metabolism is controlled by the sparteine/debrisoquine gene locus.
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  • 31
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    European journal of clinical pharmacology 31 (1986), S. 79-83 
    ISSN: 1432-1041
    Keywords: amikacin ; aminoglycoside ; cystic fibrosis ; pharmacokinetics ; bronchial diffusion
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary 36 pharmacokinetic studies of amikacin were performed to evaluate the bronchial diffusion of amikacin in 9 children with cystic fibrosis, 3 to 15 years old. Amikacin was administered i.v. according to a variable dosage regimen. Four children without cystic fibrosis were enrolled as controls. The mean half life was 1.1, the volume of distribution averaged 0.26 l/kg, and the mean plasma clearance was 131 ml/min/1.73 m2, which no differed from that of the controls. The mean peak plasma concentration was always above the MIC but its level depended on the unit dose: 18.5 mg/l, 25,95 mg/l and 31,46 mg/l for doses of 5, 7.5 and 12.5 mg/kg, respectively. Between consecutive amikacin infusions, the plasma level was above the MIC for 21% and 46% of the time after the 5 and 7.5 mg/kg doses. The maximum concentration in sputum between H1 and H2 was always below the MIC, except after 15 mg/kg. The ratio AUC sputum/AUC plasma was between 0.028 and 0.61, and it increased from the beginning to the end of the course of treatment. No side effects were observed on hearing, or vestibular and renal function. The results are used to suggest more appropriate dosing regimens.
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  • 32
    ISSN: 1432-1041
    Keywords: allopurinol ; benzbromarone ; oxipurinol ; pharmacokinetics ; repeated dose ; drug interaction ; urate excretion
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Previous studies have described a pharmacokinetic interaction between probenecid, a uricosuric drug, and oxipurinol, the major metabolite of allopurinol. In single dose studies, no interaction was found to occur between benzbromarone, another uricosuric agent, and oxipurinol. A cross over study was conducted in 12 volunteers to compare the kinetics of allopurinol and oxipurinol following treatment for 7 days with allopurinol alone or combined with benzbromarone 20 or 100 mg. The pharmacokinetic parameters of allopurinol were not modified by the uricosuric therapy, but those of oxipurinol were markedly altered by concurrent administration even of the lower dose of benzbromarone; the average plasma level fell by 30% and the renal elimination rate was increased by 50%. A parallel increase in the renal elimination rate of uric acid was observed (significant only with the higher dose of benzbromarone) and a positive linear correlation between the fractional excretion of uric acid and that of oxipurinol was established.
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  • 33
    ISSN: 1432-1041
    Keywords: trimazosin ; proteinuria ; chronic renal insufficiency ; hypertension ; glomerular filtration rate ; renal vascular resistance ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The kinetics and short-term (10 weeks) effects of trimazosin, an alpha1-adrenoreceptor antagonist, on renal function and blood pressure in patients with moderate chronic renal insufficiency and hypertension, have been studied for the first time. Eight patients in whom the blood pressure was not normalized with a diuretic alone underwent pharmacokinetic studies and assessment of the renal function during a 10-week period of trimazosin therapy. Trimazosin significantly lowered blood pressure (recumbent and upright) without significantly altering renal function. Renal vascular resistance was decreased by 14%. Fractional sodium excretion, proteinuria and laboratory serum tests remained unchanged. Neither body weight nor pulse rate were affected. Moderate renal insufficiency did not modify the pharmacokinetics of the drug. Thus, trimazosin, as second-step antihypertensive agent, appeared to be safe and effective in patients with moderate renal insufficiency and hypertension, without exerting favourable or adverse renal effects during short-term therapy.
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  • 34
    ISSN: 1432-1041
    Keywords: salbutamol ; asthma ; controlled release tablets ; chronic obstructive lung disease ; pharmacokinetics ; therapeutic effect
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In a double-blind cross-over study 20 patients with reversible airways obstruction were treated either with conventional 4 mg tablets of salbutamol a.i.d., or 8 mg controlled release (CR) tablets of salbutamol b.d. Each treatment was given for 2 weeks. The morning PEFR was significantly higher with the CR tablets (p〈0.05) but although the evening PEFR was also better the difference was not significant. Wheeze was significantly lower (p〈0.05) and extra “rescue” inhalation of bronchodilators was required less often and on fewer occasions during treatment with the CR tablets. Comparison of the 12-h mean plasma salbutamol profile showed a peak and trough every 6 h with the standard tablets, and a flatter profile with a single, lower and delayed peak during the 12 h between CR tablets. Although the minimum and average plasma salbutamol levels were similar in the groups on the two preparations, the maximum plasma level was significantly lower and there was significantly less fluctuation on CR tablets (p〈0.02). The CR and standard tablets had equivalent bio-availability.
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  • 35
    ISSN: 1432-1041
    Keywords: ceftriaxone ; dialysis ; continous ambulatory peritoneal dialysis ; pharmacokinetics ; intraperitoneal administration ; intravenous administration
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The kinetics of ceftriaxone was investigated in 8 patients without infection, who were receiving continuous ambulatory peritoneal dialysis (CAPD). Ceftriaxone 1 g was injected i.v. and 1 g was given intraperitoneally in the CAPD fluid during a 4-h dwell time. Ceftriaxone was assayed by HPLC. After intravenous administration, the kinetic parameters of ceftriaxone were: plasma t1/2, 12.3 h, total plasma clearance, 14.0 ml/min, volume of distribution at steady state 0.18 l/kg, and peritoneal clearance 0.59 ml/min. Over 72 hours only 5.5% of the dose was eliminated by the peritoneal route. After intraperitoneal administration, ceftriaxone rapidly appeared in serum; the absorption t1/2 was 1.1 h and the mean peak concentration was 38.8 µg/ml. The absorption of ceftriaxone from the peritoneal space was 39%. A single 1.0 g IP dose led to serum and dialysate concentrations of ceftriaxone above the minimum inhibitory concentration for susceptible pathogens for 24 hours.
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  • 36
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    European journal of clinical pharmacology 31 (1986), S. 1-7 
    ISSN: 1432-1041
    Keywords: torasemide ; diuretic activity ; pharmacokinetics ; healthy subjects ; side-effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Torasemide 40 mg/day p.o. was administered for 21 days to 8 healthy volunteers to investigate its pharmacodynamics, pharmacokinetics and safety on chronic administration. It induced a highly significant initial increase in 24-h urinary volume and 24-h excretion of sodium and chloride, but its affect diminished after the first days. On Days 0, 1, 10 and 21 the experiement was divided in 3 clearance phases, extending from 0 to 2 h, 2 to 6 h and 6 to 24 h after dosing. The fractional excretion of sodium, chloride, potassium, calcium, magnesium and inorganic phosphates peaked during the first 2 h and returned almost to the control value during the following two clearance phases. The phase-dependent changes were significant for all electrolytes, except for potassium and inorganic phosphate. Plasma electrolyte levels remained constant throughout the study, except for a small decrease in chloride and potassium and for an increase in calcium and magnesium. Fasting blood glucose and glucose tolerance test were unaffected. A small but significant decrease in LDL-cholesterol was observed on Day 10. Other plasma lipid components showed minor changes. Plasma uric acid levels were moderately increased. There was no significant change of the creatinine clearance. Body weight fell significantly (by about 2 kg) during the study. Tonal audiometry was normal before and after the study. There was no significant difference between the plasma levels of torasemide on Days 1, 10 and 21, nor between its elimination half-life on Days 1 and 21. Side-effects consisted mainly of fatigue and low-back pain on days of intense diuresis. There were no toxic symptoms. ECG recordings and blood pressure remained within normal limits.
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  • 37
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    European journal of clinical pharmacology 31 (1986), S. 49-51 
    ISSN: 1432-1041
    Keywords: torasemide ; pharmacokinetics ; kidney insufficiency
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The plasma concentration of torasemide was determined as a function of time in 8 patients with impaired renal function (creatinine clearance ⩽25 ml/min). The elimination half-life (1.3 to 3.8 h), the volume of distribution (0.12 to 0.29 l/kg), and the total body clearance (0.02 to 0.10 l/kg·h) were similar to those observed in normal volunteers.
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  • 38
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    European journal of clinical pharmacology 31 (1986), S. 53-55 
    ISSN: 1432-1041
    Keywords: torasemide ; renal failure ; haemodynamics ; clearance ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The concentration of Torasemide in plasma, dialysate and ultrafiltrate were determined during one haemofiltration and three dialyses. Results show that Torasemide is not significantly eliminated from the blood by these technics.
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  • 39
    ISSN: 1432-1041
    Keywords: nicardipine ; angina pectoris ; haemodynamic ; pharmacokinetics ; radionuclide studies
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Pharmacokinetic, haemodynamic and radionuclide studies explored the acute pharmacokinetic and pharmacodynamic actions of nicardipine in patients with coronary heart disease. Nicardipine infusion resulted in dose-related reductions in systolic and diastolic blood pressure and an increased heart rate. Pharmacodynamic activity was evident between 12 and 24 min following 5 and 10 mg i.v. nicardipine but by 3–6 min following the higher doses of 15 and 20 mg; hypotensive activity persisted for up to 2 h. Post-infusion nicardipine concentrations declined biexponentially; however the limited data precluded formal compartmental analysis. Plasma clearance ranged from 5–12 ml/min/kg, and appeared lower than previously reported volunteer data. The haemodynamic actions of nicardipine (10 mg infusion over 10 min) in 6 patients undergoing diagnostic catheterization were reductions in systolic, diastolic and mean systemic arterial pressure and systemic vascular resistance index. Heart rate and stroke volume index increased, and there was a small but statistically significant increase in pulmonary artery occluded pressure. Radionuclide parameters were measured in 20 patients with stable angina, at rest and during supine bicycle exercise, before and 3–5 min after nicardipine 10 mg intravenously. The left ventricular ejection fraction increased by 4% at rest but not during exercise. The left ventricular rest and exercise ejection and filling rates both increased with a concurrently reduced left ventricular ejection time. There was a highly significant inverse relationship between baseline exercise ejection fraction and the response to nicardipine; ejection fraction increased with low initial values but was either unchanged or fell with higher initial values. These data suggest that the acute effects of nicardipine in stable coronary artery disease probably reflect a reduction in left ventricular afterload and an associated augmentation of cardiac pumping performance. The acute circulatory profile of nicardipine appears sufficiently promising to warrant longer-term studies in ischaemic heart disease.
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  • 40
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    European journal of clinical pharmacology 29 (1986), S. 697-701 
    ISSN: 1432-1041
    Keywords: tenoxicam ; renal insufficiency ; non-steroidal antiinflammatory agents ; protein binding ; metabolism ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of tenoxicam after a single oral dose of 20 mg has been studied in 12 patients with various degrees of decreased renal function. Unchanged tenoxicam and its 5′OH-metabolite in plasma and urine were determined by HPLC. The mean areas under the plasma concentration-time curve (138±53 µg/ml·h) and terminal half-lives in patients with impaired renal function did not differ from values previously reported in normal volunteers, nor did the peak concentration of tenoxicam. The half-life of 5′OH-tenoxicam and unchanged tenoxicam where the same. The urinary excretion of 5′OH-tenoxicam fell with decreasing renal function. Thus no dosage adjustment should be necessary and the usual daily dose of tenoxicam may be administered once daily also to patients with renal failure.
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  • 41
    ISSN: 1432-1041
    Keywords: tetrabenazine ; hydroxytetrabenazine ; pharmacokinetics ; bioavailability ; active metabolite ; movement disorder
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of tetrabenazine and a metabolite, hydroxytetrabenazine, have been investigated in seven patients being treated for involuntary movement disorders. Tetrabenazine had a very low oral systemic availability (mean 0.049±0.032 SD). First-pass metabolism to hydroxytetrabenazine was extensive, and the systemic availability for this metabolite was high (mean 0.81±0.30 SD). Since hydroxytetrabenazine has been reported to be as active as tetrabenazine in depleting brain amines, and is present at much higher plasma concentrations than the parent drug, it is likely that this metabolite is the more important therapeutic moiety.
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  • 42
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    European journal of clinical pharmacology 29 (1986), S. 721-723 
    ISSN: 1432-1041
    Keywords: domperidone ; levodopa ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effect of simultaneous oral administration of 20, 40, or 80 mg domperidone on the pharmacokinetics of an oral 500 mg dose of levodopa was studied in eight normal women. No significant differences in maximum plasma levodopa concentration, the time of its attainment, or the area under the plasma levodopa concentration versus time profile occurred. Domperidone significantly reduced the incidence of adverse gastrointestinal effects due to levodopa administration.
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  • 43
    ISSN: 1432-1041
    Keywords: phenobarbital ; propylhexedrine salt ; barbexaclone ; bioavailability ; pharmacokinetics ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The kinetics of phenobarbital (PB) was compared after oral administration of equivalent doses of the drug as the acid or the propylhexedrine salt (barbexaclone) to 7 normal volunteers. The absorption and elimination parameters were very similar. It was concluded that propylhexedrine did not affect the serum kinetics of PB given as barbexaclone.
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  • 44
    ISSN: 1432-1041
    Keywords: enprofylline ; theophylline ; bronchial reactivity ; histamine inhalation test ; healthy volunteers ; pharmacokinetics ; bronchodilatation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In a double blind, placebo controlled, crossover study the pharmacokinetics and acute effects of enprofylline and theophylline on airway reactivity during histamine challenge were investigated in 10 healthy volunteers. The pharmacokinetic parameters of enprofylline were (mean): elimination half-life 1.9 h, total body clearance 191.1 ml · kg−1 · h−1, volume of distribution 0.48 l · kg−1, and protein binding 49%. Bronchial reactivity in the histamine inhalation test was expressed as the concentration causing a 20% fall in FEV1.0 (PC20). Mean PC20 values were lowest after placebo and highest after theophylline with the enprofylline values in between. Only the difference in PC20 Safter placebo and theophylline was statistically significant (p〈0.05). At the time of determination of the PC20, the serum concentration of enprofylline was between 16.5 and 11.8 µmol/l, and that of theophylline was between 78.3 and 61.1 µmol/l. Adverse actions of enprofylline were nausea (3/10) and cardiovascular reactions (2/10), whereas theophylline mainly caused restlessness (3/10) and tremor (2/10). Thus enprofylline, in one-fifth of the serum concentration of theophylline cannot be regarded as equipotent in terms of bronchoprotection.
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  • 45
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    European journal of clinical pharmacology 30 (1986), S. 113-120 
    ISSN: 1432-1041
    Keywords: theophylline ; pharmacokinetics ; stable isotopes ; diurnal variation ; single dose administration ; multiple dose administration ; systemic availability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Theophylline, enriched with the stable isotopes13C and15N, was administered intravenously in a dose of 10 mg to 8 healthy men following single (200 mg) and multiple (200 mg 8-hourly for 5 days) oral dose administration of aminophylline. Total plasma clearance, volume of distribution, and half-time determined from the intravenous data were similar, demonstrating that the pharmacokinetics of theophylline after chronic dosing can be predicted from the pharmacokinetics of a single dose. With chronic oral dosing, however, the mean trough concentration was 12% higher at 9 a.m. than at 5 p.m., the end of the dose interval (3.94±0.55 vs. 3.50±0.45 µg·ml−1). The AUC following oral dosing was 25% higher in the multiple dose study than in the single dose study. Simulation analysis suggested that these results could be explained by diurnal variation in the clearance or absorption rate or a combination of both. Thus, the systemic availability of theophylline measured during a single dosage interval after chronic oral dosing to steady state would be overestimated in comparison with that measured after a single oral dose.
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  • 46
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    European journal of clinical pharmacology 30 (1986), S. 187-190 
    ISSN: 1432-1041
    Keywords: isosorbide dinitrate ; haemodialysis ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In 10 patients with end stage renal disease on regular haemodialysis the plasma concentrations and dialyzer clearance of isosorbide dinitrate (ISDN) were determined after an oral dose of a retarded release formulation of 60 mg ISDN. The maximal plasma concentration of ISDN 2–7 h after oral administration was higher (14 ng/ml) than has been reported in healthy volunteers. The haemodialyzer clearance of ISDN was 92.4 ml/min at a blood flow of 200 ml/min and dialysate flow of 500 ml/min. During a 5-h haemodialysis an average of 0.3 mg ISDN was removed from the patient's circulation, representing about 0.5% of the administered dose and about 3% of the available drug in the circulation. No influence of haemodialysis on the plasma level of ISDN was found.
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  • 47
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    European journal of clinical pharmacology 30 (1986), S. 205-208 
    ISSN: 1432-1041
    Keywords: cisapride ; diazepam absorption ; drug interaction ; pharmacokinetics ; pharmacodynamics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effects of the benzamide cisapride (C) (8 mg) i.v. have been compared to placebo (P) in a double blind randomised study. The effects on gastric emptying, the absorption and effects of oral diazepam, and BP and pulse were observed. Cisapride increased the rate of gastric emptying of 500 ml liquid containing diazepam 10 mg (t1/2 C: 7.4 min, P: 14.9 min). The initial rate of absorption of diazepam contained in the drink was increased by C (AUC 0–1 h C: 328 µg h 1−1, P: 253 µg h 1−1, but there was no change in overall bioavailability. This change in diazepam kinetics was associated with a significantly greater impairment in reaction time in the first 45 min after drinking but not in self rated sedation. Cisapride produced a significant tachycardia (e.g. after 10 min C: 82 beats/min, P: 69 beats/min) which probably reflects a peripheral vasodilator action. Cisapride may therefore alter the pharmacokinetics and dynamics of concurrently administered drugs.
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  • 48
    ISSN: 1432-1041
    Keywords: cefodizime ; skin suction blister fluid ; pharmacokinetics ; protein binding ; healthy subjects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Cefodizime pharmacokinetics was investigated, evaluating drug concentrations in serum, skin suction blister fluid (SBF), saliva and urine in six healthy male subjects who were administered a 1-g dose intravenously. Serum levels in five subjects can be described according to a two-compartment open model; terminal half-life is 181±14 min. Volume of distribution (Vdβ) amounts to 15.3±1.61, serum clearance to 59±6 ml/min, renal clearance to 33±3 ml/min. Of the administered dose, 54% is renally excreted unchanged within 27 h. Unbound drug fraction in serum is 19.0% and in SBF 38.4%. Thus renal clearance of free cefodizime amounts to 172 ml/min, Vdss to 68.91 (free drug). Whereas cefodizime has not been detected in saliva samples, SBF concentration 3–9 h post administration parallel serum levels, amounting to 40% of the respective serum concentration. At 9 h, unbound cefodizime concentrations in SBF amount to 1.4±0.4 µg/ml, this value being well above the MIC90% values of many clinically relevant bacteria.
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  • 49
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    European journal of clinical pharmacology 30 (1986), S. 407-416 
    ISSN: 1432-1041
    Keywords: malotilate ; cirrhosis ; bioavailability ; liver fibrosis ; metabolite kinetics ; pharmacokinetics ; portal-systemic shunting ; urinary metabolites
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Malotilate, a sulphur-containing compound with antifibrotic and hepatoprotective properties in several animal models, has been investigated in cirrhotic patients. Nine patients with cirrhosis of various aetiologies and severity, and 4 healthy volunteers, participated in a pharmacokinetic study. After a single dose of 500 mg malotilate p.o. peak malotilate plasma concentration measured by GC-MS was 35 times higher in patients (median 0.70 µg/ml) than in controls (median 0.019 µg/ml). The median apparent oral clearance was approximately 50 times lower in cirrhotics (median 2.2l/min) than in healthy volunteers (118l/min). The apparent oral clearance was significantly correlated with indicators of portalsystemic shunting, such as the 2-h postprandial serum bile acids and the bioavailability of oral nitroglycerine. Urinary output of the glucuronidated metabolite-(M3), measured by HPLC, was normal in patients, whereas recovery of metabolite-M6 (resulting from ring opening and loss of sulphur) was reduced. Six patients in an open 6-month trial received malotilate 200 mg t.i.d. for 2 months and 400 mg t.i.d. for 4 months. The thrombocyte count increased and serum ferritin level fell in all patients, and serum cholinesterase rose and IgA decreased in 5 of 6. The other indicators of liver function did not show a significant change. Dry skin was the only possible adverse effect. It is concluded that first-pass elimination of malotilate is dramatically reduced in cirrhotics, and that a smaller amount of the drug reaches the liver in such patients. Malotilate was well tolerated, even in patients with advanced disease.
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  • 50
    ISSN: 1432-1041
    Keywords: cefotiam ; pharmacokinetics ; clearance ; urinary excretion ; biliary excretion
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Six patients, aged 52 to 71 years, with T-tube drainage of the common bile duct and a urinary catheter after cholecystectomy, were studied in order to evaluate the urinary and biliary excretion and pharmacokinetics of cefotiam in the early postoperative period. Each patient received cefotiam 1 g i.v. as a bolus injection. Cefotiam in plasma, urine, and bile were determined by HPLC. A 2-compartment open model with elimination from the central compartment satisfactorily fitted the plasma levels of the drug. The renal clearance of cefotiam (CLR=133 ml/min) was an order of magnitude greater than its biliary clearance (CLB=11.8 ml/min). Glomerular filtration was the main mechanism for elimination of cefotiam. The values of CLR and CLB in relation to the total plasma clearance (CL=138. ml/min) demonstrated the negligible role of metabolism in elimination of cefotiam in these patients.
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  • 51
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    European journal of clinical pharmacology 30 (1986), S. 445-451 
    ISSN: 1432-1041
    Keywords: ceftriaxone ; cholecystectomy ; cephalosporins ; biliary excretion ; T-drain bile ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Three groups of patients with biliary tract disease treated by cholecystectomy were given ceftriaxone. In Group 1 single doses of 150 mg and 1500 mg were given on Days 1 and 5 after cholecystectomy. In Group 2 2 g was given daily for 6 days and the cholecystectomy was on Day 2. Patients in Group 3 received 2 g every 12 h for 3 to 5 doses before cholecystectomy. Plasma samples, urine and T-drain bile were collected at various times from Groups 1 and 2 patients. Gallbladder bile and plasma were collected from Group 3 patients at the time of cholecystectomy. The mean (±SEM) T-drain bile-to-plasma concentration ratio of ceftriaxone in Groups 1 and 2 was 6.7±0.92. The mean (±SEM) gallbladder bile-to-plasma concentration ratio was 33±4.2. No clinically significant differences were detected between the kinetics of ceftriaxone in the cholecystectomy patients compared to normal volunteers. The usual dosage of ceftriaxone appeared adequate for prophylaxis or treatment of biliary tract infection by susceptible organisms.
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  • 52
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    European journal of clinical pharmacology 30 (1986), S. 433-438 
    ISSN: 1432-1041
    Keywords: fluocortolone ; pharmacokinetics ; adrenal suppression ; cortisol suppression
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of fluocortolone and its effect on plasma cortisol levels are described after oral administration of 20, 50 and 100 mg to 9 healthy adults. The concentrations of fluocortolone and cortisol in plasma were measured simultaneously by HPLC with UV detection. Fluocortolone was rapidly absorbed after all doses, giving the maximum plasma level after 1.4–2.1 h. After ingestion of 20, 50 and 100 mg, the peak levels were 199, 419 and 812 ng/ml, respectively. The maximum plasma levels and areas under the plasma level-time curves increased in proportion to the dose. Post-maximum plasma levels declined monoexponentially with a half-life of 1.76 h. Plasma half-life (t1/2=1.76 h), volume of distribution (1.03 l/kg) and oral clearance (6.9 ml/min/kg) were independent of the dose. The intensity and duration of adrenal suppression was dose dependent. Maximum suppression was observed 8 hours after fluocortolone. Clearcut suppression of cortisol levels after 24 hours was only seen following 100 mg fluocortolone.
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  • 53
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    European journal of clinical pharmacology 30 (1986), S. 453-456 
    ISSN: 1432-1041
    Keywords: methotrexate ; psoriasis ; pharmacokinetics ; p.o. ; i.m. administration ; methotrexate steady-state ; erythrocyte concentration
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Methotrexate (MTX) concentrations in erythrocytes in 32 psoriatics treated weekly with MTX p.o. or i.m. have been studied. When treatment had been constant for at least 5 weeks, there was only small variation in erythrocyte MTX (ery-MTX) in the week between two courses of treatment. The ery-MTX was correlated with the weekly dose of MTX. For patients treated with MTX i.m.r=0.87, and in patients given divided oral dosesr was 0.68. There was no difference in ery-MTX between the two routes of administration. No correlation was observed between ery-MTX and the total MTX dose or the length of treatment. During constant MTX administration small variations in ery-MTX were observed. Small changes in the weekly dose of MTX resulted in marked changes in ery-MTX in 4 of the 5 patients studied.
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  • 54
    ISSN: 1432-1041
    Keywords: urapidil ; pharmacodynamics ; pharmacokinetics ; hypertension
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The study was designed to follow the haemodynamic effects and pharmacokinetics under steady-state conditions of three different doses of urapidil infused continuously. Nine male hypertensive patients received three randomly assigned intravenous infusions of 32.5, 65 and 130 mg urapidil, over 14 h during 6 consecutive days, in a change-over fashion. Blood pressure and heart rate were measured over a period of 28 h after the infusion began and were compared with a reference profile obtained prior to the treatment periods. Urapidil and its main metabolite, parahydroxylated urapidil, were also determined for 28 h after the infusion began using HPLC. The 32.5 mg dose of urapidil caused a maximum decrease in systolic blood pressure of 33±8 mmHg, the 65 mg dose a maximum decrease of 39±12 mmHg and the 130 mg dose a maximum decrease of 50±12 mmHg. The 32.5 and 65 mg doses resulted in similar serum urapidil concentrations, with maximum levels in the 100 to 200 ng/ml range, and the 130 mg dose caused a maximum level approximately four times that achieved with the 32.5 mg dose. The serum concentration of parahydroxy urapidil was proportional to the corresponding dose of urapidil. Four patients reported mild headache, fatigue, weakness, pressure in the head, perspiration and orthostatic dysregulation. The side-effects were probably drug related but required no specific therapy. In summary, the 32.5 mg dose of urapidil resulted in a pronounced decrease in blood pressure. The average pressure reduction over the 14-h infusion period showed further dose-dependent increases after the 65 and 130 mg doses. In severe hypertension, the 130 mg dose can be employed, since it does result in a further, significantly larger decrease in blood pressure.
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  • 55
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    European journal of clinical pharmacology 30 (1986), S. 567-574 
    ISSN: 1432-1041
    Keywords: morphine ; lung clearance ; pharmacokinetics ; physiological model ; diabetes mellitus ; postoperative state
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The influence of lung uptake and lung clearance on the disposition of morphine was studied in surgical patients. In the postoperative period morphine was given intravenously by a two-rate infusion regimen. Under steady-state conditions samples of mixed central venous blood (pulmonary artery) and peripheral arterial blood (radial artery) were taken simultaneously and at the same time cardiac output was measured. The concentration differences between venous and arterial blood were used to calculate the extraction ratio of morphine across the lung. In all patients there was marked pulmonary uptake, but the concentration differences in most of them were small under steady-state conditions. The extraction ratio (mean ±SD) across the lung was 0.06±0.10, implying insignificant lung clearance. However, in two patients, both with diabetes mellitus, there was a significant concentration gradient, indicating that the lung could contribute to the total body elimination of morphine. On the other hand, the total clearance was similar in diabetic and nondiabetic patients (1190 and 1150 ml/min, respectively), implying that pulmonary clearance would have no significant influence on the kinetics of morphine. A physiologically based pharmacokinetic model was used to describe the disposition of morphine in postoperative patients. The model allowed simulation of pulmonary diffusion, uptake and elimination and supported conclusions based on model-independent experimental data.
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  • 56
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    European journal of clinical pharmacology 30 (1986), S. 597-605 
    ISSN: 1432-1041
    Keywords: ceftazidime ; renal failure ; dosage adjustment ; predicted serum level ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Ceftazidime has good antibacterial activity against many Gram-negative micro-organisms including Ps. aeruginosa. The aim of the present study was to calculate a dosage adjustment regimen for renal failure patients and to test it in a second group of patients. A study was made of the pharmacokinetics of ceftazidime 1 g given as a single bolus i.v. injection in 20 patients in an intensive care unit with varying degrees of renal function, including patients on regular haemodialysis. The serum half-life of elimination (t1/2β) varied from 1.6 to 45 h depending on renal function. During haemodialysis the mean t1/2 was 4.7 h. A good correlation between the renal clearance of creatinine and ceftazidime was observed. In most patients protein binding was lower than previously observed. From the pharmacokinetic data, a dosage adjustment regimen for patients with renal insufficiency was calculated, which studies in 7 further patients showed to be effective.
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  • 57
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    European journal of clinical pharmacology 30 (1986), S. 619-623 
    ISSN: 1432-1041
    Keywords: acenocoumarol ; cimetidine interaction ; stereoselectivity ; healthy subjects ; pharmacokinetics ; anticoagulant effect
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The kinetics and dynamics of single doses (5 mg p.o.) of the optical isomers of acenocoumarol (R-AC and S-AC) were followed in healthy subjects and the effect on them of cimetidine 800 mg/day was also investigated. The AC enantiomers differed greatly in their pharmacokinetics. The mean residence time (MRT) of R-AC was about 10 times longer than that of S-AC, 15 h vs 1.2 h. There was no difference in the volume of distribution. Depression of blood clotting activity (Thrombotest) was observed only after administration of R-AC. The inactivity of S-AC as a vitamin K antagonist must be ascribed to its short MRT. Cimetidine did not affect the acute oral kinetics of R- and S-AC, nor did it affect the anticlotting activity of R-AC. The urinary excretion pattern of the 6- and 7-hydroxylated AC metabolites was not altered during cimetidine treatment. Although the present studies showed no effect of cimetidine on the pharmacokinetics and dynamics of acenocoumarol, the findings of Serlin et al. [3] suggest that cimetidine should not be administered during acenocoumarol therapy.
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  • 58
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    European journal of clinical pharmacology 30 (1986), S. 629-631 
    ISSN: 1432-1041
    Keywords: adriamycin ; epirubicin ; anthraquinone glycosides ; pharmacokinetics ; chemotherapy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The plasma pharmacokinetics of adriamycin and 4'epi-adriamycin have been studied in 6 patients with ovarian carcinoma after simultaneous intravenous administration of equal amounts of the two anthracyclines. A highly selective liquid chromatographic analytical method permitted quantification of plasma concentrations of the two drugs as well as their corresponding 13-hydroxy metabolites. The plasma concentrations of each drug followed a three-compartment open model, with great interindividual variation in the pharmacokinetic parameters. On average, the area under the plasma concentration time curve (AUC) and the maximum plasma concentration (Cmax) were 1.6- and 1.2-times larger for adriamycin than for 4'epi-adriamycin. 4'Epi-adriamycin was eliminated faster than adriamycin by 4 of the 6 patients, the average terminal half-life of the latter being 1.4-times longer. The plasma concentrations of the 13-hydroxy metabolites did not exceed 20 ng/ml. Their AUC values averaged 23% of those of the intact drugs.
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  • 59
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    European journal of clinical pharmacology 30 (1986), S. 635-636 
    ISSN: 1432-1041
    Keywords: theophylline ; etophylline ; diurnal variations ; i.v. application ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
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  • 60
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    European journal of clinical pharmacology 30 (1986), S. 641-647 
    ISSN: 1432-1041
    Keywords: pinacidil ; hypertension ; vasodilators ; renal function and — haemodynamics ; beta-blockers ; guanidines ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The acute and chronic effects of pinacidil on blood pressure (BP) and renal function were investigated in 10 patients with moderate arterial hypertension insufficiently controlled by chronic beta-blockade. Acute i. v. administration of pinacidil caused a significant fall in BP of 29.9/18.3 mm Hg and, despite beta-blockade, a concomitant rise in heart rate (HR) of 21%. Renal vascular resistance (RVR) showed a marked reduction as a consequence of the fall in BP, and a transient rise in renal plasma flow (RPF). Diuresis and renal clearance of sodium and uric acid showed a parallel fall. The excretion rates of albumin and β2-microglobulin were also significantly reduced. Pharmacokinetic studies indicated that glomerular filtration was responsible for elimination of the parent drug, and that proximal tubular secretion was the pathway of excretion of the main metabolite, pinacidil pyridine-N-oxide. During therapy for 4 months there was no further significant reduction in BP, despite increases in the daily dose of pinacidil. The effects on HR were less conspicious after 4 months; renal haemodynamic parameters and body weight were not significantly changed. The initial level of RVR and the initial acute reduction in this parameter appeared to be major determinants of the long-term BP response. The drug was well tolerated apart from one patient who developed slight fluid retention. However, concomitant administration of a diuretic will probably be necessary during routine use of this therapeutic combination.
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  • 61
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    European journal of clinical pharmacology 30 (1986), S. 699-704 
    ISSN: 1432-1041
    Keywords: bevantolol ; pharmacokinetics ; young and elderly subjects ; metabolite ; accumulation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of bevantolol were examined following single and repeated oral doses to young and elderly volunteers. Following administration of a single 200-mg bevantolol tablet mean maximum plasma bevantolol concentrations in young and elderly subjects were 1690 ng/ml and 1810 ng/ml, respectively. Maximum bevantolol concentrations occurred approximately 1.1 h postdose in both young and elderly subjects. There were no significant differences in mean steady state bevantolol concentrations on Day 14 between young and elderly subjects. However, disproportionate increases in Cmax, and in AUC, but not in tmax values were observed between Days 1 and 14. On Days 1 and 14, most young and elderly subjects exhibited monoexponential decline in bevantolol plasma concentrations after absorption phase. In those subjects Day 14 elimination half-lives in young and elderly were 1.9 and 2.2 h, respectively. In subjects who exhibited biexponential decline in bevantolol, an age effect in elimination became apparent, on Day 14 elimination half-lives were 5.7 and 11.2 h in young and elderly subjects, respectively. Bevantolol Metabolite III concentrations were observed in plasma of some subjects during the first 6 h after dosing. At steady-state AUC (0-ldc) values for the metabolite were less than 2% those of bevantolol. Bevantolol plasma levels accumulate to a small extent with repeated 200 mg daily doses. This is probably due to the contribution of a late and more persistent terminal elimination phase that was discernable in only certain individuals.
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  • 62
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    European journal of clinical pharmacology 30 (1986), S. 713-717 
    ISSN: 1432-1041
    Keywords: cefmenoxime ; peritoneal dialysis ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The kinetics of the aminothiazolyliminomethoxy cephalosporin, cefmenoxime, were determined after a 30 min intravenous infusion of 15 mg/kg body weight in 6 adult subjects undergoing continuous ambulatory peritoneal dialysis. Concentrations of cefmenoxime in serum, urine and dialysate were determined by high-pressure liquid chromatography. The mean peak serum concentration was 92.8±11.6 µg/ml and the harmonic mean for the elimination half-life was 5.46 h. The volume of distribution at steady-state was 14.60±3.01 l/kg. Total body clearance of the drug was 31±7.7 ml/min with 8±5% and 5.75±2.72% of the administered dose being eliminated by renal and peritoneal clearance, respectively. Peritoneal clearance for all exchanges (n=24) was 1.93±68 ml/min. These data suggest that peritoneal losses of this drug are minimal and doses conventionally employed in advanced renal failure can be utilized in the management of systemic infections.
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  • 63
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    European journal of clinical pharmacology 30 (1986), S. 731-734 
    ISSN: 1432-1041
    Keywords: benzylpenicillin ; intravenous administration ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary We have studied the pharmacokinetics of intravenously administered benzylpenicillin in normal subjects during bedrest and during ambulation. The values of total body clearance, mean residence time, and renal clearance found during ambulation were 487.4±100.5 ml/min, 36.23±13.45 min, and 309.4±93.4 ml/min (means ± SD). The corresponding values for bedrest were 543.6±122.6 ml/min, 35.27±10.21 min, and 324.1±145.3 ml/min. There were no significant differences between any of these pharmacokinetic variables with the change in posture. These results differ from previously reported results for the effects of posture on the pharmacokinetics of penicillins administered by extravascular routes, and suggest that the absorption of benzylpenicillin may be dependent on posture.
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  • 64
    ISSN: 1432-1041
    Keywords: atrial natriuretic polypeptide ; α-hANP ; pharmacokinetics ; radioimmunassay
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary We have analysed the pharmacokinetics ofα-human atrial natriuretic polypeptide (α-hANP) in healthy subjects, using a two-compartment open model following bolus intravenous injection. The plasma half-times for the fast and slow components were 1.7±0.07 min and 13.3±1.69 min respectively. V1 (the volume of the central compartment), Vz (volume of distribution) and Vss (volume of distribution at steady-state) were 5370±855 ml (89.5±14.3 ml·kg−1), 32000±4620 ml (533±77.0 ml·kg−1), and 11900±1530 ml (198±25.5 ml·kg−1) respectively. The mean plasma clearance was 1520±121 ml·min−1 (25.4±2.0 ml·min−1·kg−1.
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  • 65
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    European journal of clinical pharmacology 31 (1986), S. 165-168 
    ISSN: 1432-1041
    Keywords: bromerguride ; dopamine antagonist ; pharmacokinetics ; pharmacodynamics ; prolactin level ; side-effects ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The plasma levels and urinary excretion of the dopamine antagonist, bromerguride, were measured by radioimmunoassay in healthy male volunteers given 50 µg i.v. and oral doses of 1 and 2 mg. Plasma prolactin was also measured by radioimmunoassay. Following i.v. injection, the concentration of bromerguride declined biphasically, with half-lives of 7 min and 1.2h. The total clearance was 32 ml·min−1·kg−1 and the apparent volume of distribution was 3.6 l/kg. The bioavailability of oral bromerguride was 29% after 1 mg and 25% after 2 mg. The drug was almost totally metabolized and less than 0.05% of the dose was excreted in urine in 24 h after oral administration. Plasma prolactin levels were increased in a dose-dependent manner for about 8 h. Side-effects were minimal, mainly being tiredness and headache in some of the volunteers.
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  • 66
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    European journal of clinical pharmacology 31 (1986), S. 169-175 
    ISSN: 1432-1041
    Keywords: glycerol-1-nitrate ; plasma concentration ; pharmacokinetics ; urinary excretion
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The plasma kinetics and urinary excretion of glycerol-1-nitrate (G-1-N), a water soluble metabolite of glycerol trinitrate with anti-anginal potential, have been investigated in healthy human volunteers following oral doses of 10, 20 and 40 mg tablets and 20 mg as drops. In all volunteers G-1-N was rapidly absorbed. The mean concentration-time curves peaked 40 min after administration of tablets at 144 ng/ml (10 mg), 308 ng/ml (20 mg) and 573 ng/ml (40 mg). After the drops the peak of 324 ng/ml occurred at 1 h. The areas under the G-1-N concentration-time curve and the G-1-N peak heights were linear with dose. Tablets and drops can be regarded as bioequivalent with respect to area under the curve and elimination half-life. The bioavailability of the 20 mg tablet relative to the 20 mg drops was 98.6% in terms of area under the curve. The mean apparent half-life of G-1-N elimination from plasma was 2.69±0.67 h (n=46). The mean residence time of G-1-N in the body was 4.65 h compared to 0.28 h for glycerol trinitrate after buccal administration. Female volunteers were found to have significantly lower areas under the curve than male volunteers. The difference was probably due to differences in body weight. Renal excretion does not play an important role in the elimination of oral G-1-N from the body. An overall average of 5.42% of the G-1-N dose was excreted in the urine; free drug accounted for 4.02% and conjugated drug for 1.40%.
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  • 67
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    European journal of clinical pharmacology 31 (1986), S. 191-194 
    ISSN: 1432-1041
    Keywords: tiapride ; Huntington's disease ; pharmacokinetics ; tardive dyskinesia
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of tiapride were determined at steady-state in 5 patients with tardive dyskinesia and 2 patients with Huntington's disease given tiapride 100 mg t.i.d. for 7 days. The maximum serum concentration of tiapride of 1.47±0.35 µg/ml was reached after 1.4±0.67 h. The half-life time of elimination was 229±41 min. About 50% of the dose of tiapride was excreted unchanged by the kidney. Neither protein binding nor glucuronide, sulphate or acetyl conjugation was observed. Renal clearance in the patients appeared to be lower but the other pharmacokinetic parameters did not differ from previous findings in healthy young volunteers.
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  • 68
    ISSN: 1432-1041
    Keywords: primaquine ; malaria ; acute and chronic dosing ; carboxylic acid metabolite ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of primaquine (PQ) and its major carboxylic acid metabolite (PQC) have been studied in seven Indian patients withP. vivax malaria following PQ 15 mg/day p.o. for 14 days. After a single oral dose on Day 1, a mean peak blood concentration of 50.7 ng/ml PQ was attained after 2.3 h, which declined monoexponentially with a half-life of 5.6 h. The mean total body clearance was 37.6 l/h and the volume of distribution was 2921. The mean renal excretion (0–24 h) of the drug was only 0.54% of the dose and renal clearance was 0.189 l/h. Following chronic administration, none of the pharmacokinetic parameters was affected, and a steady state blood concentration of 2.5–4.2 ng/ml PQ was attained. After the first dose of PQ, PQC had a mean area under the blood concentration — time curve 11-fold higher than that of the parent drug. In contrast to the rapid distribution and elimination of PQ, the metabolite showed a longer mean residence time and accumulation in the body. The mean Cmax and AUC of the metabolite on Day 14 were 48 and 40% higher than the corresponding Day 1 values. The metabolite could not be detected in urine at any time in any patient. PQ and its metabolite did not show any accumulation in blood cells.
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  • 69
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    European journal of clinical pharmacology 31 (1986), S. 217-222 
    ISSN: 1432-1041
    Keywords: N-acetylcysteine ; bioavailability ; slow-release formulation ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary N-Acetylcysteine was given intravenously and as three fast dissolving and one slow-release formulation, on separate occasions, as a single dose of 600 mg to 10 fasting (5 men and 5 women) healthy volunteers. Blood and urine were sampled for the following 12 h. Renal clearance constituted around 30% of total body clearance, which was 0.21 l/h/kg. Volume of distribution was 0.33 l/kg, consistent with distribution mainly to extracellular water. The late elimination half-life was 2.27 h and the mean residence time 1.62 h. The slow-release tablet resulted in a flattened plasma concentration-time curve typical of slow release formulations, while the other three oral formulations were rapidly absorbed. The oral availability of N-acetylcysteine varied between 6 and 10%, with the slow-release tablet having the lowest and the fast dissolving tablet the highest availability.
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  • 70
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    European journal of clinical pharmacology 31 (1986), S. 231-233 
    ISSN: 1432-1041
    Keywords: betaxolol ; pharmacokinetics ; middle aged subjects ; oral and i.v. administration
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of betaxolol was studied in 8 middle-aged (40–60 years) subjects after oral (20 mg) and intravenous (10 mg) administration. The principal parameters were almost identical to those observed in young healthy volunteers. The recommended therapeutic regimen, a single daily dose of 20 mg, appears well suited for middle aged, hypertensive patients.
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  • 71
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    European journal of clinical pharmacology 31 (1986), S. 239-242 
    ISSN: 1432-1041
    Keywords: piroximone ; cardiotonic drug ; pharmacokinetics ; bioavailability ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Six healthy, male subjects received single intravenous and oral doses of piroximone. Plasma piroximone concentrations were assayed up to 8 h after each dose by HPLC. Urinary excretion of the parent compound was also determined. Following the oral dose, piroximone reached peak plasma concentrations within 30 to 90 min. The t1/2 of the terminal decay phase was 2.8 h, the mean apparent volume of distribution was 2.5 l/kg, and the mean total body clearance was 755 ml/min. Mean urinary recovery of parent drug within 24 h was 50% after the intravenous dose and 41% after the oral dose. Renal clearance accounted for approximately 50% of total body clearance. Oral bioavailability, estimated from AUC or urinary recovery, was 80%.
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  • 72
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    European journal of clinical pharmacology 31 (1986), S. 261-265 
    ISSN: 1432-1041
    Keywords: metoprolol ; myocardial infarction ; acute disease ; pharmacokinetics ; dosage regimen
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary A combined i.v. and oral dosage regimen of metoprolol early in acute myocardial infarction has been evaluated. Metoprolol 15 mg i.v. in three divided doses followed by 200 mg orally in divided doses was administered to 20 patients. The median delay from onset of pain to start of treatment was 7.5 h. Following the i.v. dose absorption of the first oral dose was prolonged in several patients, but the plasma metoprolol concentration rapidly stabilized at a mean of about 200 nmol/l. A significant correlation was found between the change in resting heart rate and the plasma concentration of metoprolol 15 min after the start of treatment. Blood pressure was not correlated with metoprolol concentration. Nine patients were restudied after 16–19 days of chronic therapy. The time to maximal plasma concentration of metoprolol on chronic treatment was reduced compared to that observed after the first oral dose. The median minimum plasma concentration during steady state averaged around 200 nmol/l and was comparable to the mean trough levels 24 and 48 h after the start of therapy. In the majority of patients, the dosage regimen rapidly produced and maintained plasma levels of metoprolol which should induce a significant degree of beta-blockade.
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  • 73
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    European journal of clinical pharmacology 31 (1986), S. 285-290 
    ISSN: 1432-1041
    Keywords: imipramine ; ranitidine ; cimetidine ; pharmacokinetics ; metabolism ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetic characteristics of imipramine were studied after a single, oral, 100 mg dose was taken by 12 healthy male subjects following 3 days of pretreatment with placebo, cimetidine (300 mg every 6 h), and ranitidine (150 mg every 12 h) in a randomized, double blind, crossover trial. After each imipramine dose plasma samples were collected for 72 h and assayed for imipramine, desipramine, 2-hydroxyimipramine and 2-hydroxydesipramine by HPLC. Cimetidine preadministration statistically prolonged imipramine t1/2 compared to ranitidine (22.7 vs. 13.0 h) or placebo (10.8 h). Mean imipramine area under the curve (AUC) following cimetidine pretreatment was more than double that following placebo (2.633 vs. 0.966 µg·h·ml−1) or ranitidine (1.14 µg·h·ml−1) pretreatment. Imipramine apparent oral clearance was reduced in all 12 subjects after cimetidine. Compared to ranitidine or placebo, cimetidine pretreatment was associated with an increased imipramine/desipramine AUC ratio, suggesting cimetidine-induced impairment of demethylation of imipramine. Ranitidine was not observed to alter imipramine pharmacokinetics.
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  • 74
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    European journal of clinical pharmacology 31 (1986), S. 299-302 
    ISSN: 1432-1041
    Keywords: femoxetine ; cimetidine ; pharmacokinetics ; drug interaction ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The possibility of a pharmacokinetic interaction between femoxetine and cimetidine has been evaluated in 8 healthy volunteers. Two volunteers received single doses of femoxetine, and 6 were given multiple doses of femoxetine for 7 days with and without concurrent cimetidine. No influence of cimetidine was observed on the kinetics of single doses of femoxetine, but after multiple doses the plasma concentration of femoxetine was significantly increased. Similarly, the AUC at steady state tended to be increased, but not to a significant extent. Concurrent cimetidine did not cause a reduction in the AUC of the active desmethyl metabolite. It is recommended that femoxetine is given in reduced doses (e.g. 400 mg) when administered with cimetidine.
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  • 75
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    European journal of clinical pharmacology 31 (1986), S. 307-311 
    ISSN: 1432-1041
    Keywords: pirazolac ; rheumatoid arthritis ; transsynovial distribution ; synovial fluid drug level ; pharmacokinetics ; protein binding
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Following a washout period of 7 days, twenty-one patients suffering from rheumatoid arthritis and 3 from osteo-arthritis, who all required articular puncture were given a non-steroidal anti-inflammatory drug pirazolac 450 mg b.d. for 7 days. After discontinuation of the treatment the subjects were divided into 4 groups each of 6 patients. The non protein bound fraction of pirazolac in synovial fluid (0.86%) was significantly higher than that in plasma (0.53%). The average pirazolac concentration in plasma within the dosing interval fluctuated between 30.9 µg/ml and 59 µg/ml, and in synovial fluid between 16.6 µg/ml and 29.9 µg/ml. The half-life of pirazolac calculated from the measured and interpolated data from all patients was 30.9 h in plasma and 66.2 h in synovial fluid. The absolute free concentrations in plasma and synovial fluid (approx. 250 ng/ml) were in the range of the IC50-values for inhibition of cyclooxygenase in mouse peritoneal macrophages.
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  • 76
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    European journal of clinical pharmacology 31 (1986), S. 333-337 
    ISSN: 1432-1041
    Keywords: prazosin ; renal failure ; hypertension ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Pharmacokinetic parameters of prazosin (t1/2, tmax, Cmax and AUC have been studied in 18 hypertensive patients with varying degrees of chronic renal failure (serum creatinine ranging from 1.6 to 11.4 mg/dl). An oral dose of 2 mg of prazosin was added to the preexisting antihypertensive medication. The degree of renal impairment did not influence the peak drug concentration, the time to peak or the serum half-life. On the other hand, the hypotensive action after 2 mg prazosin, was more pronounced in patients with severe chronic renal failure. This effect could not be explained by a difference in the pharmacokinetics of prazosin in severe as compared to moderate chronic renal failure or to normal renal function.
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  • 77
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    European journal of clinical pharmacology 31 (1986), S. 351-353 
    ISSN: 1432-1041
    Keywords: digoxin ; diltiazem ; interaction ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of digoxin were studied before and after a 2 week course of diltiazem, 30 mg four times daily, in 7 healthy volunteers. Each subject received an IV dose of digoxin before starting diltiazem and again on day 15 of the study. Diltiazem was continued until all sera and urine were collected. During the control and diltiazem phases, respectively, the terminal elimination rate constants were 0.0231±0.007 h−1 and 0.0254±0.007 h−1, the volumes of distribution were 10.5±3.95 l/kg and 10.2±3.26 l/kg, and the total body clearances were 3.72±0.78 ml·min−1·kg−1 and 4.09±0.94 ml·min−1·kg−1. None of these pharmacokinetic parameters of digoxin were significantly different before or during diltiazem administration. Overall, there does not appear to be an interaction between digoxin and diltiazem.
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  • 78
    ISSN: 1432-1041
    Keywords: tiapamil ; desmethyltiapamil ; pharmacokinetics ; cardiovascular effects ; cirrhotic patients ; plasma protein binding ; impaired hepatic elimination ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Tiapamil 70 mg was administered i.v. to 8 healthy male volunteers and 8 patients (7 males, 1 female) with biopsy proven hepatic cirrhosis. Two of the patients also received 600 mg p.o. Serial plasma and urine samples were collected and the parent drug in plasma and urine and desmethyl-tiapamil in urine were assayed by a specific HPLC method. The plasma and urine data for the parent drug after i.v. and p.o. dosing were simultaneously fitted to linear p.o. and i.v. two compartment models with exit from and input into the central compartment. Absorption was assumed to be a first order process. In the volunteers the mean pharmacokinetic parameters were: 101 l for the steady-state volume of distribution, 750 ml·min−1 for nonrenal clearance, 195 ml·min−1 for renal clearance and 1.7 h for the half-life of the terminal disposition phase. The urinary recoveries of the parent drug and desmethyltiapamil averaged 21.4 and 0.8% of the dose, respectively. In the patients the steady-state volume of distribution, the amount of unchanged drug in urine and the half-life of the terminal disposition phase were significantly increased (171 l, 29.0% of the dose, 3.5 h, respectively). Decreased plasma protein binding in the patients accounted for the larger steady-state volume of distribution. The nonrenal clearance of 519 ml·min−1, tended to be smaller in the patients than in the volunteers. Together with the increased urinary recovery of tiapamil in the patients this indicates a moderately impaired elimination capacity in the cirrhotics. The renal clearance was similar in the patients (213 ml·min−1) and the volunteers. The absolute oral bioavailability of tiapamil was 55 and 49% in 2 patients. No effects of tiapamil on heart rate or supine blood pressure were detected, either in volunteers or in patients. Negative dromotropic effects were found in 2 volunteers and 2 patients after i.v. dosing.
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  • 79
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    European journal of clinical pharmacology 31 (1986), S. 463-468 
    ISSN: 1432-1041
    Keywords: naproxen ; osteoarthritis ; elderly patients ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of naproxen have been examined in 13 elderly patients (mean age 84.2 years) and in 9 younger patients (mean age 53.9 years) at the end of a 21 day course of therapy with naproxen 500 mg b.d. The mean pre-dose concentration on days 19, 20 and 21 was significantly higher in the elderly patients than in the controls (60.1 vs. 43.3 µ g · ml−1). The AUC (0–24) was significantly higher in the elderly subjects only when normalized for body weight (9.1 vs. 5.4 µg·ml−1·h kg−1 p⩽0.02). The AUC was significantly higher in the elderly group compared to the control group also in the normalized form. The apparent clearance of naproxen was reduced in the elderly compared to the control patients (315 vs. 628 ml·h−1). The percentage protein binding of naproxen was the same in both groups (99.8%) but the free concentration of naproxen was significantly higher in the elderly patients than in the control patients (141 vs. 89.8 ng·ml−1). Although there was no excess of side effects in the elderly patients it is suggested that when naproxen is given to elderly patients, therapy should be started at the lower end of the dosage range.
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  • 80
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    European journal of clinical pharmacology 29 (1986), S. 635-637 
    ISSN: 1432-1041
    Keywords: netilmicin ; prematurity ; infants ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of netilmicin were studied in 12 premature infants with proven or presumed sepsis during the first month of life. Eleven of 12 patients received netilmicin 2.5 mg/kg intravenously every 12 h while one 770-gram birth weight infant received 2.5 mg/kg every 18 h. Mean steady-state peak and trough concentrations were 8.9 µg/ml and 2.8 µg/ml, respectively. Of twelve patients, 11 had trough serum concentration above 2 µg/ml and four had trough serum concentrations above 3 µg/ml. Mean total body clearance of netilmicin was 0.84 ml/min/kg. The mean clearance of 0.72 ml/min/kg was substantially lower in patients with a mean postnatal age of 2.7 days than the clearance of 1.10 ml/min/kg in patients with a mean postnatal age of 23 days. The mean apparent volume of distribution was 0.63 l/kg; and the mean elimination half-life was 8.6 h. A three-fold interpatient variation in pharmacokinetic parameters was seen. These data suggest the need for careful monitoring of netilmicin serum concentration in premature infants.
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  • 81
    ISSN: 1432-1041
    Keywords: biperiden ; pharmacokinetics ; pharmacodynamics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics and pharmacodynamics (changes in pupil size and salivary flow) of biperiden following a single oral and intravenous dose were investigated in six normal subjects. After the injection plasma concentrations declined biphasically, with half-times of 1.5 h for the rapid phase and 24 h for the terminal phase. Clearance and apparent volume of distribution were high (12 ml·min−1·kg−1 and 24 l·kg−1 respectively). Absorption was rapid but the systemic availability was incomplete (33%), probably due to first-pass metabolism. Central nervous system (CNS) adverse effects and changes in pupil size were observed after both routes of administration while salivary flow was affected only by the injection.
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  • 82
    ISSN: 1432-1041
    Keywords: idazoxan ; pharmacokinetics ; alpha 2-adrenoceptor antagonist ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary A high performance liquid chromatographic method was developed for the quantitative determination of idazoxan in plasma. The assay was used to study the disposition of the drug after intravenous infusion and oral administration to five normal subjects. After i.v. administration the kinetics could be described by a two compartment model with a mean elimination half life of 4.20 h. The mean calculated volume of distribution during the elimination phase was 3.20 l/kg−1 and the mean plasma clearance was 824 ml min−1. After oral administration a lag period before onset of absorption was observed in all five volunteers, the plasma levels declining monoexponentially from the peak concentration with a mean elimination half life of 5.58 h. The absolute availability varied between 26% and 41% with a mean value of 34%. Invitro measurements produced a blood/plasma ratio of 1.3 for idazoxan.
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  • 83
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    European journal of clinical pharmacology 30 (1986), S. 225-230 
    ISSN: 1432-1041
    Keywords: dexamethasone ; pharmacokinetics ; dose dependancy ; suppression of cortisol ; healthy females
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The dose dependency of the pharmacokinetics of dexamethasone and its influence on the endogenous secretion of cortisol has been studied in healthy females. The maximum plasma level occurred between 1.6 and 2.0 h after doses of 0.5–3.0 mg independent of the type of administration. AUC, distribution volume, plasma clearance and cmax did not increase in proportion to the dose but only by the factor of about 0.6–0.7 after the oral administration of 0.5–1.5 mg. Comparatively high values were reached after 3.0 mg i.m. This may be due to reduced bioavailability of the oral doses. Within the first 12 h after the administration of 0.5–3.0 mg, endogenous cortisol secretion was influenced independent of dose. However, the suppressive effect after 24 h was dose dependent and amounted to approximately 24% for 0.5 mg p. o., 62% for 1.5 mg p. o. and 90% for 3.0 mg i. m. In the case of administration every second day, the integral reduction within 24 h after the administration of 0.5 mg dexamethasone was 44 to 65% and for 1.5 mg between 59 and 62%.
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  • 84
    ISSN: 1432-1041
    Keywords: methotrexate ; hydroxymethotrexate ; lymphoid malignancy ; renal excretion ; metabolism ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In children with lymphoid malignancies 18 courses of methotrexate (18–200 mg/kg) administered as a 24-h infusion were monitored. Plasma concentrations and renal excretion rates of methotrexate (MTX) and 7-hydroxymethotrexate (7-OHMTX) were determined. A low correlation was found between the administered dose of MTX and the body exposure to MTX or 7-OHMTX. Although 84% of the MTX eventually recovered from the urine was excreted during the 24 h of the infusion, the renal clearance of MTX was markedly lower during the time of the infusion than after it. There were courses with a low and others with a high renal clearance of MTX during the infusion, despite the same urine flow. A low MTX renal clearance was correlated with a high body exposure to MTX. As the same variations were also seen in the same patient during successive courses, pharmacokinetical characterization of patients appears questionable. The renal clearance of 7-OHMTX was significantly lower than the renal clearance of MTX, and the body exposure to 7-OHMTX ranged from 2–40% of the MTX body exposure. Treatment courses with a low or a high body exposure to 7-OHMTX were not associated with different urinary recoveries of the metabolite. Differences in MTX hydroxylation could not be substantiated. Because the concentration of 7-OHMTX is high soon after the end of an infusion, a specific method of MTX determination should be chosen for controlling treatment.
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  • 85
    ISSN: 1432-1041
    Keywords: metronidazole ; metabolism ; pharmacokinetics ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The influence of dose and route of administration on the kinetics of metronidazole and its major metabolites has been investigated in 8 healthy volunteers given 0.5 and 2.0 g i.v. and p.o. Metronidazole elimination kinetics from plasma could be described by an open two-compartment model. The systemic oral bioavailability of both doses was approximately 1. The total systemic clearance of the intravenous 2.0 g dose was 9% lower than that of the 0.5 g dose (p〈0.05). There were no significant dose-related differences in volume or rate of distribution. The elimination half-life was similar after the four treatments with metronidazole. The major elimination pathways, renal excretion and hepatic oxidation and glucuronidation, accounted for more than 2/3 of the total systemic clearance. Clearance both by hepatic oxidative metabolism and renal excretion was significantly lower after 2.0 than after 0.5 g i.v., whereas there was no significant difference after the oral doses. The results indicate that a high therapeutic dose of metronidazole may be eliminated at a reduced rate, but this is probably not of clinical importance. No single saturable elimination pathway was identified.
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  • 86
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    European journal of clinical pharmacology 30 (1986), S. 489-491 
    ISSN: 1432-1041
    Keywords: cimetidine ; digoxin ; drug interference ; urinary excretion ; ulcer patients ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Cimetidine inhibits the renal tubular secretion of creatinine and digoxin is partly excreted by the same pathway. In order to investigate a possible interaction between the two drugs, a randomized cross-over acute study has been conducted. Six patients with duodenal ulcers were given a single dose of digoxin (Dig) 0.75 mg i.v. with and without oral cimetidine 1200 mg/day. Cimetidine significantly reduced creatinine clearance from 157 to 132 ml/min. There was no significant difference in inulin clearance, 99.2 vs 97.5 ml/min, Dig elimination half life 53.9 vs 56.9 h, apparent volume of distribution 11.3 vs 11.6 l/kg, systemic clearance 2.42 vs 2.35 ml/min/kg, renal clearance 1.48 vs 1.62 ml/min/kg or urinary excretion of digoxin 49.5 vs 51.6% of dose without or with cimetidine. These results suggest that cimetidine does not influence the disposition of digoxin.
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  • 87
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    European journal of clinical pharmacology 30 (1986), S. 499-501 
    ISSN: 1432-1041
    Keywords: clometacin ; prostaglandin ; renal excretion ; plasma renin activity ; pharmacokinetics ; non steroidal antiinflammatory agents ; cyclooxygenase inhibitor
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In 6 healthy subjects the effect of clometacin on renal function, sodium and water excretion, plasma renin activity and urinary excretion of prostaglandins has been studied. After four days of treatment with clometacin, the excretion of urinary prostaglandins E2, F2 α and 6 keto F1 α and thromboxane B2 were reduced by 61.2, 41.2, 59 and 42%, respectively. 62% reduction in plasma renin activity was also observed. There was no significant change in mean blood pressure, heart rate, body weight, creatinine clearance or urinary excretion of sodium. It is concluded that clometacin is an efficient cyclooxygenase inhibitor in healthy individuals with a normal sodium intake, and that caution is required when giving clometacin to patients at risk of developing renal failure during treatment with a cyclooxygenase inhibitor.
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  • 88
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    European journal of clinical pharmacology 30 (1986), S. 527-533 
    ISSN: 1432-1041
    Keywords: digoxin intoxication ; antibody treatment ; pharmacokinetics ; clearance ; distribution volume
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary 17 patients with severe digoxin intoxication were successfully treated with 320 to 480 mg Fab fragments of digoxin-specific IgG from sheep. The infusion period ranged between 0.5 and 7 h. Serum and urine concentrations of digoxin bound to Fab fragments, and in 11 cases unbound Fab fragments in serum, were determined during and after the infusion. The renal clearance of bound digoxin and therefore of the antibody was 13.6 ml/min. The median extrarenal clearance of the Fab fragments was 10.9 ml/min. The half-life of the serum concentrations starting at 12 h was 14.3 h, and the value was increased to 25.4 h when regression began at 24 h; the corresponding apparent distribution volumes were 25.9 and 541. These figures exceed the volume of the extracellular space and suggest intracellular penetration of the Fab fragments. The dosage of the antibody should be sufficiently high to bind digoxin in the most severe cases of poisoning. The maximum serum concentrations of bound antibody were 30 mg/l after 3 h and 20 mg/l after 5 h. A loading dose of 160 mg followed by an infusion of 0.5 mg/min was sufficient to absorb digoxin re-diffusing into the serum during the first 8 h. In some cases free digoxin reappeared in the serum 8–12 h after beginning the treatment. This might be prevented by infusing a further ampoule at a rate of 0.1 mg/min or less.
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  • 89
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    European journal of clinical pharmacology 30 (1986), S. 575-579 
    ISSN: 1432-1041
    Keywords: morphine ; pharmacokinetics ; intrathecal-intravenous administration ; flip-flop kinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Morphine concentrations in plasma in five patients following intrathecal (i.t.) administration and in five other patients following intravenous (i.v.) administration were measured by a specific RIA sensitive to 0.1 ng/ml. Pharmacokinetic analysis showed a similar apparent total body clearance of morphine following both i.t. and i.v. administration, and complete bioavailability of i.t. morphine to the systemic circulation. This indicates that morphine is probably not metabolised in the CNS and that all of an i.t. dose diffuses from CSF to the plasma compartment. However a marked decrease in the i.t. terminal rate constants, involving a flip-flop phenomenon, contributed to the prolonged terminal half-life of i.t. morphine. The slow diffusion of morphine from the i.t. space to the plasma compartment can account for the prolonged analgesia following i.t. administration.
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  • 90
    ISSN: 1432-1041
    Keywords: codeine ; morphine ; pharmacokinetics ; steady-state ; oral administration
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Plasma concentrations of codeine and its demethylated metabolite, morphine, were determined after single and repeated oral administration of codeine. Twelve healthy volunteers received two doses of codeine 60 mg, 2.8 h apart. In order to achieve steady-state conditions codeine 60 mg was then taken every 8 h for a further five doses. The plasma concentrations of codeine and morphine after the first, second and seventh doses were analyzed by GC-MS. The maximum plasma concentrations of codeine and morphine were reached about 1 h after administration and this time interval did not change on repeated administration. The peak plasma codeine was higher after the second dose of codeine than after the first and the concentration resembled that at steady-state. For morphine, the plasma concentration did not increase significantly after the second dose. Both after a single dose and during steady-state the plasma concentration of morphine was only 2–3% of that of codeine. It seems unlikely that morphine plays a significant role in the analgesic efficacy of single or repeated doses of codeine.
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  • 91
    ISSN: 1432-1041
    Keywords: TZU-0460 ; renal failure ; H2-receptor antagonist ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary We have studied pharmacokinetics of a new H2-receptor antagonist, TZU-0460, in patients with varying degrees of renal impairment. The apparent volume of distribution at steady-state was 1.70 l/kg, and the plasma protein binding of TZU-0460 or its active metabolite, desacetyl TZU-0460 was less than 10% in normal subjects. These variables were not altered with renal impairment. Sixty percent of TZU-0460 given orally was excreted via the kidney, mainly by tubular secretion. The half-time of elimination was 3.94 h in normal subjects, and was prolonged to 12.13 h in severe renal failure (creatinine clearance below 30 ml/min/1.48 m2). Dosage adjustment of TZU-0460 is necessary in renal failure.
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  • 92
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    European journal of clinical pharmacology 31 (1986), S. 33-40 
    ISSN: 1432-1041
    Keywords: metoclopramide ; high dose ; antiemetic efficacy ; cancer patients ; pharmacokinetics ; cisplatin
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Fifteen cancer patients receiving cisplatin-containing chemotherapy participated in two antiemetic studies. In Study 1 they received standard antiemetics in low doses on demand, and in Study 2 the same patients participated in an open randomized cross-over study between metoclopramide 1 and 2 mg/kg i.v.×5. Serum metoclopramide was determined by HPLC. Self-reporting of nausea using a visual analogue scale (VAS) was compared with observer rated scores. Tolerability and volume vomited were assessed by nurse observers. The biological half-life of metoclopramide was 9.9 h, the volume of distribution was 9.9 l/kg and the clearance was 0.68 l/h/kg. The pharmacokinetics of high dose metoclopramide was linear in the range 0.15–2 mg/kg×5, with very little accumulation. Compared to standard antiemetics, both high dose regimens of metoclopramide had a significant effect on nausea, but no effect on the volume vomited. Self reports of nausea were significantly correlated with observer rated values. Tolerance of high dose metoclopramide was good except in 3 patients who left the study because of restlessness and trismus. It is concluded that high dose metoclopramide probably can be administered for several consecutive days without appreciable accumulation of the drug. Self-reporting of nausea by patients on VAS is a simple and feasible method of evaluation. The finding that metoclopramide affects nausea but not vomiting supports the hypothesis that nausea and vomiting should be evaluated separately in assessing antiemetic efficacy.
    Type of Medium: Electronic Resource
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  • 93
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    European journal of clinical pharmacology 31 (1986), S. 23-26 
    ISSN: 1432-1041
    Keywords: sulphasalazine ; Pentasa ; slow release preparation ; 5-aminosalicylic acid ; ileo-rectal anastomosis ; ulcerative colitis ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of 5-aminosalicylic acid (5-ASA) from sulphasalazine (SASP) and the slow-release 5-ASA preparation Pentasa was investigated in a cross-over study in 9 otherwise healthy patients with an ileo-rectal anastomosis. The 24-hour recoveries of the drugs were 90.5% and 84.7%, respectively. The median release of 5-ASA from SASP was 50% and from Pentasa 75%. Equal amounts of 5-ASA (18.0% vs 17.9%) were found in the faeces, and a significantly larger amount (4.4% vs 28.9%) of the metaboliteN-acetyl-5-aminosalicylic acid (ac-5-ASA) was found in faeces following Pentasa. A larger amount of 5-ASA was absorbed and subsequently excreted in the urine, mainly as the metabolite (2.5% vs 20.5%) from Pentasa. This confirms previous results in ileostomized patients treated with Pentasa. The present findings also demonstrate that bacterial azo-reduction of SASP in patients with ileorectal anastomosis may be an adequate way to deliver 5-ASA in this type of patient. Both treatments may be used in these patients during a flare up of ulcerative colitis, but randomized studies are needed.
    Type of Medium: Electronic Resource
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  • 94
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    European journal of clinical pharmacology 31 (1986), S. 113-115 
    ISSN: 1432-1041
    Keywords: flusoxolol ; multiple-dose ; pharmacokinetics ; Ro 31-1118 ; optical isomer
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Flusoxolol (Ro 31-1411) is the pharmacologically active optical isomer of Ro 31-1118, a potent cardioselective β-adrenoceptor antagonist with partial agonist activity. It was given to 6 healthy volunteers in a single dose, 40 mg, and then in multiple doses, 40 mg daily for 8 days. Plasma concentration data were best described by a linear two-compartment pharmacokinetic model with first order absorption, and the results confirmed linear kinetics. Pharmacokinetic data for flusoxolol were comparable to those for the racemate Ro 31-1118.
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  • 95
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    European journal of clinical pharmacology 31 (1986), S. 123-124 
    ISSN: 1432-1041
    Keywords: ceftriaxone ; biliary excretion ; cholecystectomy ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Type of Medium: Electronic Resource
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  • 96
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    European journal of clinical pharmacology 31 (1986), S. 155-163 
    ISSN: 1432-1041
    Keywords: hypertension ; verapamil ; norverapamil ; pharmacokinetics ; dosing frequency
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Twelve hypertensive patients (WHO Stage I-II) were given oral verapamil (Isoptin) b.d. or t.d.s. as long-term treatment. The pharmacokinetics of verapamil and norverapamil were studied both after single and b.d. and t.d.s. doses of verapamil 240, 360 or 480 mg daily adjusted according to the blood pressure response. The apparent oral clearance of verapamil was decreased after both the twice and thrice daily dosage regimens (1.38 and 1.841/min, respectively) as compared to the single dose (4.39 l/min). The plasma half-life of verapamil was increased from 3.34 h (single dose) to 4.65 h (b.i.d.). Decreased elimination of norverapamil was also found after multiple doses of verapamil, as shown by an increase in the adjusted AUC of norverapamil (adjusted to a verapamil dose of 80 mg), namely from 574.9 h·ng·ml−1 (single dose) to 1172 h·ng·ml−1 (b.d.) and to 841 h·ng·ml−1 (t.d.s.). The plasma half-life of norverapamil increase from 5.68 h to 7.34 h during twice daily dosing. During thrice daily verapamil, no increase in plasma half-life was found either for verapamil or norverapamil, probably due to the relatively short sampling time (6 h). The plasma concentration of verapamil and the reduction in supine systolic and diastolic blood pressure were correlated. The mean decrease in supine systolic blood pressure was 5.8 mm Hg per 100 ng verapamil/ml plasma, and for diastolic pressure 2.9 mm Hg per 100 ng verapamil/ml plasma. The mean steadystate plasma concentrations of verapamil were similar after twice and thrice daily dosing regimens, which agrees with the clinical observation that blood pressure control in hypertensive patients is as good after verapamil b.d. and t.d.s.
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  • 97
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    European journal of clinical pharmacology 31 (1986), S. 177-182 
    ISSN: 1432-1041
    Keywords: glibenclamide ; bioavailability ; pharmacokinetics ; dissolution ; hypoglycaemia ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary A study has been carried out investigating four different marketed oral preparations of glibenclamide, correlating the effectiveness of the drug in these preparations in lowering plasma glucose concentrations with (i) the in vitro dissolution of the drug, measured by the British Pharmacopoeal and Desaga methods, and (ii) the in vivo bioavailability, assessed in 12 healthy human volunteers. The two dissolution methods yielded different rank orders of ease of dissolution of the drug from the various preparations; the findings of neither dissolution method correlated adequately with the results of the in vivo bioavailability studies, which correctly predicted the abilities of the preparations to reduce plasma glucose concentrations. Relative to an oral glibenclamide solution the bioavailabilities of the drug from three tablet preparations were 0.69, 0.49 and 0.24. The mean elimination half-life of the drug was 1.5 h and assuming complete bioavailability of the drug from oral solution the mean systemic clearance was 0.095 l kg−1h−1, and the mean apparent volume of distribution was 0.20 l kg−1. It is concluded that it may be unsafe to use in vitro dissolution data as a basis for assessing the bioequivalences of different glibenclamide preparations intended for oral use.
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  • 98
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    European journal of clinical pharmacology 31 (1986), S. 211-216 
    ISSN: 1432-1041
    Keywords: cyclosporin A ; absorption ; pharmacokinetics ; healthy subjects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Extensive pharmacokinetic (PK) profiles after oral dosing of 300 mg cyclosporin A (CsA) were determined in whole blood by radioimmunoassay (RIA) in 14 healthy male volunteers, using two-compartment models with either first order (M1) or zero order (M0) absorption. According to zero order absorption the mean of the following PK parameters was determined: terminal half-life=12.1±5.0 h, apparent volume of distribution at steady-state=5.6 ±2.1 l · kg−1, apparent clearance=0.51±0.11 l · h−1 · kg−1. The time lag between drug ingestion and first blood level was short, 0.38±0.11 h. Drug absorption lasted for 2.8±1.6 h. The end of absorption was indicated in each individual by a sharp drop in blood levels. The observations support the assumption that CsA is absorbed in the upper part of the small intestine with a clear-cut termination (absorption window). This assumption may explain the high degree of variability in the bioavailability of CsA.
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  • 99
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    European journal of clinical pharmacology 31 (1986), S. 243-245 
    ISSN: 1432-1041
    Keywords: brotizolam ; plasma levels ; pharmacokinetics ; elderly patients ; multiple doses
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Plasma brotizolam levels were measured in 5 elderly patients given 0.25 mg daily. The half-life of brotizolam elimination was 6.0 h after a single dose and 6.9 h after continuous administration for 3 weeks. The brotizolam concentration in plasma 2 h after the dose was 3.5 and 3.4 ng/ml, respectively, on the first and last days of the study. Brotizolam levels measured several times during the study 10 h after dosing were between 1.2 and 1.8 ng/ml. Thus, administration of brotizolam 0.25 mg/d to elderly patients for 3 weeks led neither to its accumulation nor to faster elimination. The half-life of brotizolam elimination in elderly patients was in the upper range of that found in young volunteers.
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  • 100
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    European journal of clinical pharmacology 31 (1986), S. 327-331 
    ISSN: 1432-1041
    Keywords: ceftazidime ; cholecystectomy ; pharmacokinetics ; biliary tree tissue level
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary After administration of ceftazidime as a 1 g i.v. bolus injection, its concentration was measured by HPLC at frequent intervals in serum, bile and tissue from different parts of the biliary tract in 32 patients undergoing operation for biliary tract disease. In bile from the functioning gallbladder and common bile duct, a high concentration of ceftazidime was found, mean 18.5 and 26.6 mg/l, respectively. In bile from the non-functioning gallbladder, a very low concentration was found (〈1.5 mg/l). Ceftazidime in the gallbladder wall varied considerably with the type and degree of inflammation judged histologically; the mean level was 21.3 mg/kg. The elimination half-life of ceftazidime was 1.74 h, apparent volume of distribution 20.01 and total plasma clearance 133 ml/min. In bile from T-tube specimens a high concentration was found, the mean peak values being 27.2 mg/l. However, biliary excretion of the drug was low at less than 0.5% of the administered dose. These concentrations of ceftazidime were sufficient to inhibit the in-vitro growth of pathogens, namely theEnterobacteriaecae commonly responsible for biliary tract infection.
    Type of Medium: Electronic Resource
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