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  • pharmacokinetics  (417)
  • Electron microscopy  (160)
  • Lepidoptera  (146)
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  • Springer  (833)
  • 1980-1984  (833)
  • 1925-1929
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  • 1
    Electronic Resource
    Electronic Resource
    Springer
    European journal of nutrition 22 (1983), S. 14-26 
    ISSN: 1436-6215
    Keywords: branched chain α-keto acids ; 4-methyl-2-oxopentanoate, 3-methyl-2-oxopentanoate ; 3-methyl-2-oxobutyrate ; dehydrogenation ; transamination ; pharmacokinetics ; absorption
    Source: Springer Online Journal Archives 1860-2000
    Topics: Agriculture, Forestry, Horticulture, Fishery, Domestic Science, Nutrition , Medicine
    Description / Table of Contents: Zusammenfassung Michaelis-Konstanten und Aktivitäten von Dehydrogenasen und Transaminasen der drei verzweigten α-Ketosäuren Keto-Valin, Keto-Leucin und Keto-Isoleucin in Leber, Niere, Skeletmuskel und Gehirn von Ratten werden mitgeteilt. Nach oraler Zufuhr passieren nur 11–22% der Ketosäuren unverändert die Leber. Aus pharmakokinetischen und Resorptions-Untersuchungen erhaltene Blutspiegel an Ketosäuren werden zu den Michaelis-Konstanten in Beziehung gesetzt. Bei den geringen Konzentrationen an Ketosäuren nach oraler Zufuhr kann angenommen werden, daß die oxidativen Prozesse in den nichthepatischen Geweben über die Transaminierung überwiegen. Daten über die Wachstumseffizienz von verzweigtkettigen α-Ketosäuren im Vergleich zu den entsprechenden Aminosäuren stimmen mit dieser Vorstellung überein. Bei intravenöser Verabreichung müßten die Voraussetzungen für Transaminierung besser sein als nach oraler Zufuhr. Auf der Basis von Daten aus der Literatur werden die Übertragbarkeit unserer Befunde auf den Menschen und die verschiedenen Faktoren, welche die Effizienz der verzweigten α-Ketosäuren durch Einwirkung auf ihren Stoffwechsel beeinflussen können, diskutiert.
    Notes: Summary Miehaelis-constants and enzyme activities for dehydrogenation and transamination of the three branched chainα-keto acids in liver, kidney, skeletal muscle, and brain of rats are reported. After oral load only 11–22 % of the keto acids pass the liver unchanged. Blood levels in pharmacokinetic and absorption studies are related to the Michaelis-constants. At the low keto-acid concentrations after oral application, dehydrogenation in the non-hepatic tissues is supposed to prevail over transamination. Data on feed efficiency of branched chain α-keto acids reported in the literature support this view. The chance for transamination is better after intravenous administration. The transferability of our data to humans, and various factors influencing the efficiency of branched chain α-keto acids are discussed in connection with data reported in the literature.
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  • 2
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    Springer
    Colloid & polymer science 261 (1983), S. 373-374 
    ISSN: 1435-1536
    Keywords: Electron microscopy ; short-time staining ; nodular structure ; crystallization
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Mechanical Engineering, Materials Science, Production Engineering, Mining and Metallurgy, Traffic Engineering, Precision Mechanics
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  • 3
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    Colloid & polymer science 260 (1982), S. 564-569 
    ISSN: 1435-1536
    Keywords: lin. Polyethylene ; Single crystals ; Heat of Fusion ; DSC ; Electron microscopy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Mechanical Engineering, Materials Science, Production Engineering, Mining and Metallurgy, Traffic Engineering, Precision Mechanics
    Notes: Abstract Recently published results for solution crystallized PE single crystals have shown, that the experimental heat of fusionΔH * is higher, if the solvent is exchanged to silicon oil (oil suspension samples) as compared with dried mats. This has been interpreted by the collapse of the original hollow pyramids during drying, inducing lateral defects within the lamellae. The present investigation does not confirm this unexpected result.ΔH * of dried mats (T c 66 to 91 °C) and of the corresponding oil suspension samples agree within the rather small limits of experimental error. The crystallinities as derived fromΔH *, density or WAXS are in excellent agreement. SEM micrographs of cold fractured dried mats show their spongy macromorphology, but TEM micrographs of stained ultra-thin sections reveal the lamellar morphology of the walls, consisting of curved lamellae and stacked hollow pyramides. If a dried mat is sintered at room temperature, a dense transparent film is obtained with a rather regular stacked morphology of large flat lamellae.ΔH * of these films agrees with that of the original mat.
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  • 4
    ISSN: 1570-7458
    Keywords: host-plant relations ; host variation ; Malacosoma americanum ; Malacosoma disstria ; Lasiocampidae ; Geometridae ; Lepidoptera ; niche breadth ; specialization ; plantinsect interactions
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Description / Table of Contents: Zusammenfassung Raupen von Malacosoma americanum (F.), einer oligophagen Art, die sich vor allem auf Prunus und andern baumartigen Rosaceen entwickelt, wurden verglichen mit Raupen der polyphageren Verwandten M. disstria Hb. und zwar im Hinblick auf deren Empfindlichkeit auf Unterschiede im Blatt ihrer gemeinsamen Wirtspflanze, Prunus serotina Ehrh. Das Puppengewicht und die Entwicklungszeit bis zur Verpuppung wurden gemessen bei Raupen, welche auf Blättern von freiwachsenden und von beschatteten Jungpflanzen gezüchtet worden waren. Die Blattunterschiede hatten eine ausgesprochene Wirkung, aber es gab keine Unterschiede in der Reaktion der beiden Arten. Dieser Vergleich lässt vermuten, dass die Empfindlichkeit auf intraspezifische Unterschiede der Wirtspflanzenqualität bei wirtsspezifischen und polyphagen Arten gleich ist. Indessen dürften sich laut anderen Resultaten einige Insektenarten anders verhalten.
    Notes: Abstract Larvae of Malacosoma americanum (F.)(Lepidoptera: Lasiocampidae) an oligophagous species that feeds primarily on Prunus and other rosaceous trees, were compared to larvae of the more highly polyphagous congener M. disstria Hb., with respect to their sensitivity to variation in the foliage of a common host plant, Prunus serotina Ehrh. Pupal weight and time to pupation were measured on larvae reared on foliage from open-grown and from shaded saplings. The difference in foliage had a pronounced effect, but no difference was evident between the species in their response to the variation in foliage. This comparison implies that sensitivity to intraspecific variation in host quality does not differ between host-specific and generalized species. However, results from other species suggest that some species of insects do differ in this respect.
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  • 5
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    Entomologia experimentalis et applicata 30 (1981), S. 106-110 
    ISSN: 1570-7458
    Keywords: assimilation efficiency ; growth efficiency ; niche breadth ; specialization ; hostplant relations ; plant-insect interactions ; Malacosoma americanum ; Malacosoma disstria ; Lasiocampidae ; Lepidoptera
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Description / Table of Contents: Zusammenfassung Raupen von Malacosoma americanum, einer oligophagen Art, die sich vor allem auf Prunus und andern baumartigen Rosaceen. entwickelt, wurden mit Raupen der polyphageren Verwandten M. disstria in Hinblick auf die Verwertung der Blätter ihres gemeinsames Wirtes Prunus serotina verglichen. Wirerhielten ähnliche Werte wie sie früher für andere Lepidopteren publiziert worden waren und zwar in Bezug auf die üblichen Messwerte, Anteil verwertete Nahrung, Wachstum in Trockengewicht pro Einheit gefressene oder verwertete Nahrung. Zudem unterschieden sich die beiden Arten in keiner Masszahl für Effizienz. Unsere Resultate sind im Einklang mit der Folgerung, das spezialisierte phytophage Insekten ihre Wirtspflanzen nicht besser ausnützen als as polyphage Arten tun.
    Notes: Abstract Larvae of Malacosoma americanum (F.) an oligophagous species that feeds primarily on Prunus and other rosaceous trees, were compared to larvae of the more highly polyphagous congener M. disstria Hb., with respect to the efficiency of utilization of the foliage of a common host plant, Prunus serotina Ehrh. We obtained values similar to those reported for other Lepidoptera for the commonly used measures of the fraction of ingested food that was assimilated, and for the growth in dry weight per unit of food ingested or assimilated. Moreover, the two species did not differ in any measure of efficiency. Our results are compatible with the conclusion that specialized phytophagous insects do not use their host plants with greater physiological efficiency than do generalized insects.
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  • 6
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    Entomologia experimentalis et applicata 34 (1983), S. 174-178 
    ISSN: 1570-7458
    Keywords: Lepidoptera ; Pyralidae ; Maruca testulalis ; Pod borer ; Development ; Nutritional suitability ; Host plant ; Crotalaria ; Vigna unguiculata
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Description / Table of Contents: Résumé Les possibilités de développement larvaire de Maruca testulalis sur les fleurs de huit espèces végétales ont été examinées en laboratoire. La comparaison a porté sur Crotalaria retusa, C. juncea, C. saltiana, C. misereniensis, C. mucronata, C. amazonas, Cajanus cajan et l'hôte principal de cette chenille, Vigna unguiculata. En tenant compte de la mortalité larvaire et des indices de croissance (G.I.), ces plantes ont été divisées en trois catégories principales: 1 celles provoquant une mortalité larvaire de 0–30% et ayant des G.I. ≥60%, constituent les plantes hôtes convenables (Vigna unguiculata seule); 2 les plantes qui provoquent une mortalité larvaire de 30≤50% et ont des G.I. de 30 à 60% de la plante hôte principale (Cajanus cajan, Crotalaria amazonas, C. saltiana, C. mucronata; 3 les plantes qui causent 50–100% de mortalité larvaire et dont les G.I. sont inférieurs à 30% de la plante hôte principale (Crotalaria retusa, C. juncea, C. misereniensis). Les résultats déjà publiés sur les choix du lieu de ponte des femelles et l'utilisation de C. juncea comme plante piège, sont discutés à la lumière de ces données nouvelles.
    Notes: Abstract Flowers of eight plant species were evaluated under laboratory conditions for their suitability as larval growth media for the cowpea pod borer, Maruca testulalis. The plants tested were Crotalaria retusa, C. juncea, C. saltiana, C. misereniensis, C. amazonas, Cajanus cajan and the principal host of the borer, Vigna unguiculata (cowpea), was included for comparison. Based on the data obtained on larval mortality and growth indices (GI) the plants were divided into 3 categories namely: I: Those causing 0–30% mortality and having GI value ≥60% form suitable host plants. This group only included V. unguiculata. — II: Those plant species causing 30≤50% larval mortality and having GI value 30%≤60% of the principal host plant (Cajanus cajan, Crotalaria amazonas, C. saltiana, C. mucronata). This group of species is marginally suitable as hosts. — III: Plants causing 50–100% larval mortality and having GI value ≤30% of principal host plant (C. retusa, C. juncea and C. misereniensis). Previously published data on the oviposition preference of the adult moth are discussed in the light of the present findings and the use of C. juncea as a possible trap crop.
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  • 7
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    Entomologia experimentalis et applicata 34 (1983), S. 203-205 
    ISSN: 1570-7458
    Keywords: Lepidoptera ; Sesiidae ; Synanthedon vespiformis ; Paranthrene tabaniformis ; Chamaesphecia empiformis ; Chamaesphecia tenthrediniformis ; Attractants ; Pheromones ; Clearwing moths ; Nemapogon
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
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  • 8
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    Entomologia experimentalis et applicata 30 (1981), S. 280-292 
    ISSN: 1570-7458
    Keywords: Allozyme variation ; Lepidoptera ; Yponomeuta padellus ; evolutionary stages ; F-statistics ; panmixis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Description / Table of Contents: Résumé Le degré de différenciation génétique en allozymes à des niveaux divers de divergence évolutive (populations conspécifiques, sibling species et non-sibling species) d'Yponomeuta a été déterminé. Les distances génétiques entre des sibling species ou des non-sibling species sont très larges. Il en est conclu que de telles estimations ne fournissent pas beaucoup d'informations sur le phénomène de spéciation même. Des coéfficients de reproduction consanguine (F ST) ont été calculés pour des populations d'Y. padellus provenant de six plantes-hôtes. La valeur moyenne F STest .030±.012. Les valuers de F ST des populations recueillies sur Crataegus, (plante-hôte habituelle d'Y. padellus), sont inférieures 2–3.5 fois à celles des populations de l'ensemble des autres plantes-hôtes. L'apparition de races en fonction de l'hôte, mesurée par les différences importantes dans de fréquences des allozymes entre populations sympatriques sur plusieurs plantes-hôtes, a été examinée dans quatre régions. Il apparaît ainsi que la formation de races en fonction de l'hôte se produit chez Y. padellus et que la spéciation sympatrique est un évènement très vraisemblable.
    Notes: Abstract The amount of genetic differentiation at various levels of evolutionary divergence (conspecific populations, sibling species and non-sibling species) in Yponomeuta was determined. Genetic distances between siblings or non-siblings were found to cover a wide range. It is concluded that such estimates do not give much information on the speciation process itself. Inbreeding coefficients were calculated for populations of Y. padellus from a total of six host plants. The grand mean F ST value is 0.030±0.012. F ST values for populations sampled from Crataegus, the common food plant of Y. padellus, are 2–3.5 times smaller than those for populations from the other food plants taken together. Host race formation, as measured by significant differences in allozyme frequencies between sympatric populations on two or more food plants, was investigated in four areas. Host race formation seems to occur in Y. padellus and sympatric speciation is a likely event.
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  • 9
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    Springer
    Entomologia experimentalis et applicata 34 (1983), S. 20-26 
    ISSN: 1570-7458
    Keywords: Dioryctria abietella ; Cone pyralid ; Lepidoptera ; Pyralidae ; Sex pheromone, (Z,E)-9,11-tetradecadienyl acetate ; Single sensillum recordings ; Electroantennography ; Gas chromatography ; Mass spectrometry
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Description / Table of Contents: Résumé L'analyse en chromatographie gazeuse associée à une détection électroantennographique a montré que l'acétate (Z,E)-9,11-tétradécadiényle (Z,E)-9,11–14:Ac est l'un des composants de la phéromone de Dioryctria abietella Schiff (Lepid.: Pyralidae). Couplage chromatographie en phase gazeuse spectrometrie de masse a montré la présence d'acétate tétradécadiényle avec un spectre de masse et un indice de rétention identiques au Z,E-9,11–14:Ac Un récepteur cellulaire sensible à la fois au Z,E-9,11–14:Ac et à un extrait de la femelle a été identifié sous l'antenne du mâle. Les analyses des antennogrammes et de la cellule isolée ont étayé la caractérisation du composant de la phéromone comme étant Z,E-9,11–14:Ac. Un récepteur cellulaire additionnel sensible à l'acétate (Z.)-9-tétradécadiényle et à l'acétate (Z.E.)-9,12-tétradécadiényle a été trouvé sur l'antenne du mâle, mais il n'était pas activé par l'extrait de la femelle. Sur le terrain Z,E-9,11–14:Ac, présenté seul, attirait des nombres importants de mâles de D. abietella. L'addition de l'acétate (Z)-9-tétradécényle a inhibé l'attraction des mâles par les pièges.
    Notes: Summary Gas chromatographic analyses coupled with electro-antennographic detection indicated that (Z,E)-9,11-tetradecadienyl acetate (Z,E-9, 11–14:Ac) is a pheromone component of the cone pyralid Dioryctria abietella. Gas chromatographic-mass spectrometric analyses confirmed the presence of a tetradecadienyl acetate with mass spectrum and retention index identical to Z,E-9,11–14:Ac. A receptor cell sensitive to both Z,E-9,11–14:Ac and the female extract was identified on the male antenna. An additional receptor cell sensitive to (Z)-9-tetradecenyl acetate and (Z,E)-9,12-tetradecadienyl acetate was found on the male antenna but was not activated by the female extract. In the field Z,E-9,11–14:Ac presented alone attracted significant numbers of male D. abietella. Addition of (Z)-9-tetradecenyl acetate inhibited the attraction of males to traps.
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  • 10
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    Entomologia experimentalis et applicata 36 (1984), S. 15-16 
    ISSN: 1570-7458
    Keywords: sex attractants ; Lepidoptera ; Noctuidae ; Orthosia incerta ; Orthosia cruda ; fruit pest ; Z9-14:Ac ; Z9-14:Ald ; Z11-16:Ac ; Z11-16:Ald
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
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  • 11
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    Entomologia experimentalis et applicata 34 (1983), S. 65-70 
    ISSN: 1570-7458
    Keywords: Insect growth regulators ; Anti-juvenile hormone ; Fluoromevalonate ; Precocious metamorphosis ; Premature pupation ; Ecdysis ; Fall webworm ; Hyphantria cunea ; Lepidoptera ; Arctiidae
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Description / Table of Contents: Zusammenfassung Fluormevalosäure (FMev), bekannt als ein spezifischer Inhibitor der Biosynthese des Juvenilhormons (JH) in Insekten, wurde in 0,1–50 μg/Tier Dosis topikal an 3., 4. und 5. Larvenstadien von Hyphantria cunea getestet. Die Raupen wurden auf einem semi-synthetischen, künstlichen Nährboden bei 25° und unter Langtagsbedingungen (18 : 6 St., Licht/Dunkel) gezüchtet. Diese Verbindung rief drei verschiedene Typen spezifischer Reaktionen hervor: 1) verfrühte Metamorphose, 2) gehemmte Häutung und 3) verlängerte Larvenentwicklung. Vor der verfrühten Verpuppung wurde normales Verhalten beobachtet. Die Larven des 3. oder 4. Stadiums häuteten sich meist erst nach einem interkalaren Larvenstadium in verfrühte Puppen. Unter den drei Larvenstadien erwies sich das 5. Stadium gegen die Anti-JH-Verbindung am empfindlichsten. In allen getesteten Entwicklungsphasen wiesen die frisch gehäuteten Larven die höchste Empfindlichkeit gegen FMev auf. Nach der Häutung wurde stufenweises Absinken der FMev-Empfindlichkeit beobachtet, im 5. Larvenstadium verursachte die Verbindung jedoch selbst am letzten Tag des Wachstums zu einen relativ hohen Prozentzahl verfrühte Verpuppung. Eine zweite typische Wirkung von FMev war die Hemmung der Häutungsprozesse. Zwei grundlegende Stufen der Häutungsstörungen unterschieden sich voneinander: 1) Als Folge der Anwendung hoher Dosen von FMev konnte die Mehrzahl der Raupen die alte Larvenkutikula nicht öffnen und ging deswegen in kurzer Zeit zugrunde. 2) Bei Behandlung mit niedrigen Dosen der Anti-JH-Verbindung häuteten sich einige Hyphantria-Larven scheinbar normal; nach der Häutung waren aber alle unfähig, die normalen Bewegungen und die Nahrungsaufnahme fortzusetzen. Auch die vorzeitigen Puppenhäutungen wurden in meisten Fällen durch die Anti-JH-Behandlung gehemmt. Die morphogenetischen Wirkungen von FMev konnten durch eine topikale Behandlung mit Hydroprene, einem hochaktiven JH-Analogen, vollständig oder teilweise verhindert werden.
    Notes: Summary Fluoromevalonate (FMev, ZR-3516) known as an inhibitor of JH biosynthesis was topically applied in 0.1 to 50 μg/specimen doses to the 3rd, 4th, and 5th instar caterpillars of Hyphantria cunea Drury. The anti-JH compound induced 3 main types of specific responses: 1) precocious metamorphosis, 2) inhibition of ecdysis, and 3) prolongation of larval development. Precocious pupation was accompanied by behavioural events typical of normal pupation. Third and 4th instar larvae metamorphosed prematurely mostly with the intervention of an intercalary larval instar. The 5th instar exhibited the highest sensitivity to the anti-JH agent. Within each larval stage the freshly moulted insects proved to be the most susceptible to FMev. Afterwards, the incidence of morphogenetic reaction gradually decreased with age. In another fraction of Hyphantria larvae not responding with precocious pupation, FMev evoked varying degrees of ecdysial disturbance which always resulted in the death of caterpillars. In most cases the anti-JH compound inhibited the premature pupal moult, too, and these affected insects died as tanned pharate pupae. A complete or partial “rescue” from the effects of FMev was elicited, if simultaneously or subsequently, a single topical dose of a JH analogue, hydroprene was also administered.
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  • 12
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    Entomologia experimentalis et applicata 30 (1981), S. 123-127 
    ISSN: 1570-7458
    Keywords: Sex Pheromones ; Repellent ; Heliothis armigera ; Heliothis zea ; Lepidoptera ; Noctuidae ; cotton bollworm ; corn earworm
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Description / Table of Contents: Résumé L'examen en olfactomètre a porté sur les réactions face à d'autres femelles de la même espèce, de femelles vierges ou ayant copulé d'Heliothis armigera Hübner et H. zea Boddie. Le lot comprenait 8 femelles, vierges ou ayant copulé en présence d'une femelle vierge ou ayant copulé. Les 4 combinaisons possibles de femelles vierges et de femelles ayant copulé ont été examinées avec 12 répétitions pour chaque espèce. Un extrait de l'extrémité de l'abdomen de femelles vierges d'une espèce a été présenté aux femelles de l'autre espèce pour examiner les possibilités de réactions interspécifiques aux phéromones. Pour chaque espèce, les réactions interspécifiques de répulsion entre femelles ont été hautement significatives par rapport aux témoins, à l'exception toutefois des réactions de femelle ayant copulé face à des femelles ayant elles aussi copulé. Les répulsions moyennes chez H. armigera et H. zea pour les 8 femelles de chaque expérience ont été: a) vierges en présence d'une vierge: 7,33 et 7,66; b) vierges en présence d'une femelles ayant copulé: 5,76 et 5,58; c) femelles ayant copulé en présence d'une vierge: 4,67 et 4,83. Les différences sont hautement significatives entre chaque paire de moyennes et entre chaque paire et le lot témoin; 3,17; 3,17; 3,42; 4,00 pour H. armigera; 3,17; 3,50; 2,83 et 3,75 pour H. zea. Les femelles vierges des deux espèces, H. armigera et H. zea ont présenté une réaction de répulsion en présence d'un extrait de l'abdomen de l'autre espèce; les répulsions moyennes étant respectivement 5,53 et 5,33 contre 3,83 et 3,58 pour le lot trémoin. On peut en conclure que ces répulsions doivent entraîner une tendance à la répartition uniforme.
    Notes: Abstract An olfactometer was used to determine the effect of pheromones released by females of the bollworms Heliothis armigera (Hübner) and H. zea (Boddie) on females of the same species. Four combinations of virgin and mated females were tested for repellency of one to the other. Evidence is presented that females of the two bollworms were repelled by females of the same species. In addition, extracts of virgin female abdomens of each species repelled virgin females of the other species.
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  • 13
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    Entomologia experimentalis et applicata 34 (1983), S. 155-162 
    ISSN: 1570-7458
    Keywords: Hymenoptera ; Braconidae ; Lepidoptera ; Nymphalidae ; Apanteles bignellii ; Euphydryas aurinia ; Multivoltinism ; Synchronisation ; Weather
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Description / Table of Contents: Zusammenfassung In einer Population von Euphydryas aurinia (Rottemburg) bei Oxford, England treten während einer Generation von E. aurinia drei Normalgenerationen von Apanteles bignellii Marshall auf. Jede Generation des Parasitoids kann charakterisiert werden durch das befallende Wirtsstadium und durch die aus einem Wirt schlüpfende Zahl Parasitoide. Parasitoide schlüpfen in Normalgenerationen aus dem 3., dem 4. und dem 6. Stadium des Wirts; in Ausnahmegenerationen schlüpfen sie aus dem 2. und 5. Stadium. Bis zu 70 Parasitoide können aus einer Altraupe (6. Stadium) schlüpfen und die Dauer dieses Stadiums kann bis auf 2 Wochen verlängert werden. Die Ausnahmegenerationen von A. bignellii aus Zweitlarven dürften aus Eiablagen in frühe Erstlarven stammen. Fünftlarven des Wirts, aus denen Parasitoide schlüpfen, sind ungewöhnlich klein und fressen nicht; sie dürften das Resultat sein eines Uebermasses von Apenteles-Eiern, die in frühe Viertlarven gelegt wurden. Die Synchronisation zwischen dem Parasitoiden und dem Wirt während der Zeit, da E. aurinia im Puppen-, Adult- oder Eistadium ist, wird aufrechterhalten durch ein verlängertes Coconstadium von Apanteles. Die Puppen des Parasitoiden entwickeln sich normal und die Adulten schlüpfen, bleiben aber bis 4 Wochen lang im Cocon, bevor sie sich eine Ausgangsöffnung machen. Das Wetter kann den Parasitierungsgrad der letzten Wirtsstadien beeinflussen. Wenn der Frühling kalt ist mit klarem Himmel, kann die Synchronisierung zwischen Parasitoiden, die aus Viertlarven des Wirts schlüpfen und potentiellen Fünft- und Sechtstlarven des Wirts schlecht werden. Die Entwicklung von Apanteles-Puppen wird durch die Umgebungstemperatur beeinflusst, während E. aurinia-Larven ihre Temperatur erhöhen, indem sie sich sonnen und deshalb rasch wachsen. Wenn die Parasitoiden unter solchen Bedingungen schlüpfen, sind die meisten potentiellen Wirte schon verpuppt und damit nicht mehr geeignet für die Parasitierung. Die Mechanismen der Synchronisation und der Wettereinfluss auf diese Vorgänge wird diskutiert.
    Notes: Abstract The gregarious endoparasite, Apanteles bignellii Marshall is specific to the nymphalid butterfly, Euphydryas aurinia (Rottemburg) in the British Isles. The synchronisation between host and parasitoid is described at a site near Oxford, England where both occur. Three regular generations of A. bignellii occur in one generation of the host in the studied population. Relevant features of the biology of A. bignellii and E. aurinia are described, including a method of distinguishing the number of Apanteles larval instars based upon shed cuticle remnants. Mechanisms for host-parasitoid synchronisation are outlined, especially a protracted parasitoid cocoon stage when the host is unavailable for attack during the chrysalis, adult and egg stages. Cool, but sunny weather conditions in spring can influence the degree of parasitisation experienced by final instar host caterpillars. The timing of adult A. bignellii emergence and subsequent attack on early instar hosts can lead to additional, partial, generations of parasitoids from second and fifth instar hosts.
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  • 14
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    Entomologia experimentalis et applicata 35 (1984), S. 159-167 
    ISSN: 1570-7458
    Keywords: Lepidoptera ; Geometridae ; Ectropis excursaria ; larval dispersal ; colour polymorphism ; phototaxis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Description / Table of Contents: Zusammenfassung Acht Experimente wurden durchgeführt, um einige der Faktoren zu studieren, die das Wanderverhalten der Larven (Raupen) eines polyphagen Geometriden (Ectropis excursaria (Guenée)) beein-flussen. 1. Larven sind positiv phototaktisch. Die positive Phototaxis ist negativ mit Fasten, Alter und Populationsdichte korreliert. Bei hohen Temperaturen ist sie nicht mehr nachweisbar. 2. Das Wanderverhalten der Larven wird durch die Populationsdichte beeinflußt, wodurch annähernd eine konstante Dichte erhalten bleibt. Das Verhalten der individuellen Larven is dabei nicht statistisch homogen. Es gibt ‘Wanderer’ und ‘Nicht-Wanderer’. 3. Diese Verhaltensunderschiede stehen möglicherweise im Zusammenhang mit physiologischen und morphologischen Faktoren, die den individuellen Fortpflanzungserfolg und das überleben beeinflussen können; ‘Wanderer’ sind dunkler, entwickeln sich schneller und das Gewicht ihrer Puppen ist niedriger als das der ‘Nicht-Wanderer’. 4. Eine der larvalen Farbvarianten zeigte eine Präferenz für einen von zwei angebotenen Hintergründen.
    Notes: Abstract The dispersive behaviour of larvae of a polyphagous, wide-spread geometrid (Ectropis excursaria (Guenée)) was studied by examining responses to environmental and endogenous variables. It was found that differences in behaviour can be affected by environmental factors such as light, temperature, density, and plant background as well as some physiological and morphological features. The implications of these relationships are discussed as adaptative strategies to a varying environment.
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  • 15
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    Entomologia experimentalis et applicata 35 (1984), S. 177-193 
    ISSN: 1570-7458
    Keywords: induction of feeding preference ; host plants ; non-host plants ; Manduca sexta ; Sphingidae ; Lepidoptera
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Description / Table of Contents: Résumé Vingt-deux espèces de plantes, dont 10 planteshôtes (Solanées), ont été testés comme plantes alimentaires pour des chenilles de ler stade de Manduca sexta. Sur cet ensemble, seulement 12 plantes (dont 9 plantes hôtes) induisaient la prise de nourriture et permettaient la croissance jusqu'au 5ème stade. La diversité des résultats suggère que les plantes pouvaient être classées en hôtes, non-hôtes acceptables et non-hôtes refusés. En utilisant le test du choix alimentaire préférentiel entre deux rondelles de feuilles, les chenilles néonates de ler stade ont préféré nettement les plantes-hôtes aux autres. Cette préférence initiale pour les plantes-hôtes était préservée quand les cheniles étaient élevées sur plantes-hôtes, mais devenait moins nette ou disparaissait pour des chenilles élevées sur d'autres plantes acceptées. Ainsi l'oligophagie ches M. sexta n'est pas induite, mais doit être héritée. Les chenilles néonates, aussi bien que celles de 5ème stade, présentent des préférences hiérarchisées parmi les plantes hôtes ou non. La seule frontiere nette observée était entre espèces de plantes acceptables ou non. Les hiérarchies préférentielles des chenilles du 5ème stade différaient légèrement lors-qu'elles avaient été élevées sur deux plantes-hôtes différentes. La différence essentielle était l'observation d'une préférence accrue pour l'espèce ayant servi à l'élevage, mais deux autres plantes-hôtes changaient aussi de position hiérarchique. La cause de ces changements de préférence a été approfondie, les chenilles étant élevées sur des feuilles de chaque espèce acceptable (hôte ou non). Leurs préférences alimentaires ont été définies en utilisant des combinaisons diverses (hôte x hôte, hôte x non-hôte acceptable, non-hôte acceptable x non-hôte acceptable). L'induction de la préférence alimentaires a été obtenue dans ces trois associations. Ceci montre que l'induction des choix alimentaires chez M. sexta n'est pas limitée aux plantes-hôtes. Le degré d'induction de la préférence alimentaire variait de très fort à indécelable; il dépendait de l'association examinée. La source de la variabilité de cette induction a été examinée en fonction de la relation entre la force de l'induction et les rapports taxonomiques des plantes associées. La relation obervée était inversée pour M. sexta. L'examen des données de la littérature ont révélé une relation du même type pour les autres espèces de Lépidoptères.
    Notes: Abstract Ten host plant (Solanaceae) and twelve non-host plant species were tested as foodplants for first instar larvae of the tobacco hornworm, Manduca sexta. Only nine host and three non-host plant species elicited feeding and supported growth up to fifth instar. The range of acceptability suggested that plants be divided into hosts, acceptable non-hosts, and unacceptable non-hosts. Using the two-choice feeding preference test we found that the initial preference for hosts was preserved when larvae were reared on hosts, but was less strong or absent for larvae reared on acceptable non-hosts. Thus oligophagy in the tobacco hornworm is not induced, but must be inherited. Newly-hatched first instar larvae and fifth instar larvae showed a preference hierarchy among both hosts and non-hosts. Fifth instar larvae reared separately on two different host species showed slightly different preference hierarchies among hosts. The preference for the rearing plant was increased and also two other host species changed positions in hierarchies. Feeding preferences of larvae reared on hosts or acceptable non-hosts were determined using plant combinations of host vs. host, host vs. acceptable non-host, and acceptable non-host vs. acceptable non-host. Induction of feeding preference was found in all three of these categories. This shows that induction of feeding preference in the tobacco hornworm is not restricted to host plant species. The degree to which feeding preferences were induced ranged from very strong to undetectable and dependend on the plant species paired. The strength of induction in the tobacco hornworm was found to correlate inversely with taxonomic relatedness of the plant species paired. Analysis of induction data from the literature revealed a similar correlation for other lepidopteran species.
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  • 16
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    Entomologia experimentalis et applicata 35 (1984), S. 255-261 
    ISSN: 1570-7458
    Keywords: method ; dry matter ; budget ; Lepidoptera ; phytophagous ; gravimetry ; area ; accuracy ; precision
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Description / Table of Contents: Résumé Les budgets en matière sèche consommée par des lépidoptères ont été comparés par les méthodes gravimétrique et planimétrique. La méthode gravimétrique est basée sur le rapport poids sec/poids frais de feuilles consommées par les chenilles. Avec la méthode planimétrique, la quantité d'aliment proposée aux chenilles est déterminée par les tracés de la surface des feuilles et le contenu de matière sèche par unité de surface des feuilles. La méthode de planimétrie permet l'utilisation de plus grands rameaux de feuilles et de cages d'élevage extérieures en gaze. Il n'y avait pas de différence appréciable dans les éléments du budget (croissance, ingestion et déjection), ni aucune différence dans la variabilité observée des données attribuable à la méthode utilisée. Cependant, la variabilité attendue d'après la précision des mesures avec la méthode gravimétrique est inférieure à celle de la méthode planimétrique. est inférieure à celle de la méthode planimétrique. Des éléments expérimentaux, inhérents à la méthode gravimétrique, introduisent une variabilité dans les mesures que l'on n'a pas avec la méthode planimétrique. 30–60% de la variabilité dans la consommation ont été attribués à des paramètres internes à la chenille, même quand elles provenaient toutes de la même ooplaque.
    Notes: Abstract Gravimetric and a combination areal-gravimetric methods for determining dry matter budgets for leaf eating Lepidoptera were compared. The gravimetric method is based on dry weight/live weight ratios of the leaves fed to the larvae. In the areal-gravimetric method, the quantity of food offered to the larvae is determined from the area of leaf tracings and the dry matter content per unit area of the leaves. The areal-gravimetric method permits the use of larger leaf sprays and an open, gauze enclosed rearing chamber. There were no consistent differences in budget factors (growth, ingestion or egestion), nor were there any differences in the observed variability of the data attributable to the method used. However, the expected variability based on instrument precision for the gravimetric method is less than for the areal-gravimetric method. Experimental factors inherent in the gravimetric method introduce variability to the measurements that are not present in the areal method. Thirty to 60% of the variability in budget factors was attributed to intrinsic properties of the larvae, even though the larvae were taken from the same egg masses.
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  • 17
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    Entomologia experimentalis et applicata 34 (1983), S. 121-122 
    ISSN: 1570-7458
    Keywords: Lepidoptera ; Noctuidae ; Earias insulana ; Bollworm ; Artificial diets ; Insect fecundity
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  • 18
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    Development genes and evolution 191 (1982), S. 205-207 
    ISSN: 1432-041X
    Keywords: Chitin inhibition ; Nikkomycin ; Cuticle ; Electron microscopy ; Epilachna varivestis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary The nucleoside antibiotic nikkomycin has proved to be an effective inhibitor of chitin synthesis in the Mexican bean beetleEpilachna varivestis. Ultrastructural investigations show defects in the procuticular area after nikkomycin application which suggest the complete absence of chitin. A cuticle like this is inflexible and too brittle to satisfy its normal function as an exoskeleton. The individuals are not able to free themselves from the exuvia and finally die. Therefore nikkomycin seems to be a potential insecticide with high specifity.
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  • 19
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    Calcified tissue international 33 (1981), S. 143-151 
    ISSN: 1432-0827
    Keywords: Calcium transport ; Cytochalasin B ; Dihydrocytochalasin B ; Colchicine ; Electron microscopy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine , Physics
    Notes: Summary In vivo calcium absorption was studied in normal and rachitic chicks. Cytochalasin B (CB) at a concentration of 25 µg/ml added to the medium inside the duodenal lumen inhibited calcium absorption (20 min) from 82.5±1.9% of calcium absorbed in the controls to 59.2±3% in normal and from 70.0±2.3% to 47.0±2.1% in rachitic chicks. In vitro studies by everted ileal sacs of young rabbits also showed an inhibition of active transport of calcium due to CB. Whereas in the controls the ratio of45Ca concentrations in serosal and mucosal media (60 min) was 7.2±0.32, the ratios were 5.24±0.52; 4.40±0.36; 3.40±0.42; 5.77±0.52; 1.38±0.08; and 1.06±0.02 in the presence of CB at concentrations of 5, 10 and 25 µg/ml; colchicine 10−4M, Na citrate 0.02M, and heat-devitalized conditions, respectively.45Ca concentration in the mucosal scrapings was also affected. It showed an increase from controls (15,101±404 cpm/mg) and correlated with CB concentration: 17,378±489, 19,015±1000, and 20,201±362 at 5, 10, and 25 µg/ml, respectively. Dihydrocytochalasin B also inhibited active calcium transport and caused an increase in45Ca concentration in the mucosal scrapings. Correlated electron microscopic studies showed certain changes in the brush border, especially in some actin microfilaments in the terminal web region. It seems that these morphological alterations may be related to transcytoplasmic movement of calcium.
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  • 20
    ISSN: 1432-0827
    Keywords: Alcohol ; Electron microscopy ; Growth plate
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    Topics: Biology , Medicine , Physics
    Notes: Summary We have previously demonstrated that ethanol has a direct toxic effect on the rat skeleton characterized by decreased trabecular bone volume. In the present study, we examined the ultrastructure of the distal radial epiphyseal growth plates in these same animals. Eight weeks of ethanol administration to 12 male rats results in serum alcohol levels of 140 mg/dl but did not alter the width or light microscopic appearance of the radial growth plate. Quantitative electron microscopy failed to demonstrate morphologic evidence of toxicity in the skeletal cells. We conclude that although ethanol appears to have a direct effect on rat bone characterized by enhanced resorption, toxicity is not attended by ultrastructural changes in the skeletal cells.
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  • 21
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    Calcified tissue international 33 (1981), S. 529-540 
    ISSN: 1432-0827
    Keywords: Bone cells ; Electron microscopy ; PTH ; PGE1
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    Topics: Biology , Medicine , Physics
    Notes: Summary Four different cell populations—designated PF, OB, OC, and PC—were isolated from calvaria of 18-day-old chick embryos for analysis of the effects of hormones on bone tissue. The cell populations were studied with histological and biochemical methods. Apart from the well-known cell types present in calvaria, a new cell type was found in the noncalcified organic matrix between the osteoblastic layer and the calcified matrix. These cells were provisionally called osteocytic osteoblasts. They represent the “transition state” between osteoblasts and osteocytes. On the basis of histological studies with light microscopy (LM), transmission electron microscopy (TEM) and scanning electron microscopy (SEM), the PF population was considered to originate primarily from the periosteal fibroblasts, the OB population from the osteoblasts and osteocytic osteoblasts. The population of cells still present in calvaria after removal of periosteal fibroblasts and osteoblasts was called the OC population. This cell population was very much enriched with osteocytes. The fourth isolated population (PC) was a mixed population of fibroblasts, osteoblasts, and preosteoblasts. On exposure to parathyroid hormone (PTH), all four cell populations showed increased lactate production, but only the OB and OC populations displayed increased cAMP production. Prostaglandin E1 (PGE1) stimulated cAMP production in both OB and PF cells. From the results of this study it was concluded that PTH receptors are present on all of the cell types studied, but that occupancy of the receptor induces adenylate cyclase stimulation only in osteocytes and fully differentiated osteoblasts.
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  • 22
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    Calcified tissue international 30 (1980), S. 43-50 
    ISSN: 1432-0827
    Keywords: Osteogenesis ; In vitro ; Electron microscopy ; Mineralization
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    Topics: Biology , Medicine , Physics
    Notes: Summary Chick limb mesenchymal cells differentiate into muscle, cartilage, fibrous, and bone tissue. Previous reports show that when stage 24 limb mesenchymal cells are cultured in vitro, chondrocytes, myocytes, fibrocytes, and osteoblasts can be identified on the basis of morphological and biochemical parameters. The study reported here demonstrates that phenotypic expression in culture seems to be dependent on the initial plating density, Scanning electron microscopic observations indicate that when stage 24 limb mesenchymal cells are initially seeded at high densities (5 × 106 cells per 35 mm culture dish), mounds of cells appear in culture. These mounds represent cartilage nodules composed of a fine fibrous matrix and chondrocytes, surrounded by a loose fibrous connective tissue matrix. Cultures initially plated at intermediate densities (2.0–2.5 × 106 cells/35 mm culture dish) produce a flattened layer of fibrocytes overlying a matrix of collagen fibers and calcium phosphate deposits as determined by electron-microprobe analysis; these observations are indicative of osteoblast expression. Cells seeded at this intermediate density appear larger and possess greater surface area than cells seeded at high density. It is suggested that conditions that permit such increased cell surface area coupled with a relative compaction due to cell crowding may provide conditions permissive for osteogenesis. Based on morphological criteria, it appears that chick limb mesenchymal cell osteogenesis in vitro is not associated with chondrogenesis but represents a separate route of phenotypic expression.
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  • 23
    ISSN: 1432-0827
    Keywords: Rat ; Calvarium ; Electron microscopy ; Preosteoclasts ; Osteoclasts
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    Topics: Biology , Medicine , Physics
    Notes: Summary This is a study of the fine structure of cells of the 20-day fetal rat calvarium. Special attention is given to identifying and characterizing preosteoclasts. These cells are relatively common and located largely, but not exclusively, at the endocranial bone surface. The preosteoclasts are characterized by abundant mitochondria, an incomplete perinuclear Golgi apparatus, and variable-shaped dense granules. The dense granules are unique in appearance in that they contain an internal dense matrix surrounded by a clear halo. Most granules are circular in shape but some are elongate or tubular in form. Granules with identical appearance are observed in osteoclasts. The preosteoclasts are mononucleate, or occasionally binucleate. It is suggested that because preosteoclasts are morphologically distinctive and relatively abundant, it should be feasible to separate these cells from a heterogeneous cell isolate.
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  • 24
    ISSN: 1432-0827
    Keywords: Decalcification ; Electron microscopy ; Bone matrix ; Bone glycoproteins
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    Topics: Biology , Medicine , Physics
    Notes: Summary A solution of triethylammonium EDTA in 80% ethanol was evaluated as a demineralizing reagent for bone in comparison with aqueous solutions of EDTA. Biochemical analysis and acrylamide gel electrophoresis of extracts of finely powdered bovine bone showed that most of the macromolecular components of the organic matrix extractable in aqueous EDTA were retained when the triethylammonium EDTA reagent was used. Ultrastructural examination of chick tibias decalcified with the reagents showed a better preservation of cellular morphology, especially the membranous components, and more uniformly distributed ground substance, though slightly less in quantity, when the aqueous reagent was used. Use of the two reagents appears to be complementary, the alkylammonium reagent being more appropriate for use in studies of the organic matrix of bone, including immunohistochemical studies of bone glycoproteins. The aqueous reagent is more appropriate for use in studies of cellular ultrastructure.
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  • 25
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    Calcified tissue international 33 (1981), S. 119-124 
    ISSN: 1432-0827
    Keywords: Avian eggshell ; Microstructure ; Electron microscopy ; Electron diffraction ; Calcite growth
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    Topics: Biology , Medicine , Physics
    Notes: Summary The eggshell of the domestic fowl has been studied by transmission electron microscopy and diffraction. Thin sections of shell were prepared by chemical and ion-beam thinning techniques. Each calcite column of the palisade layer consisted of crystallites of diameter 20 to 30 µm with some tendency for crystallite alignment within a single column. Evidence indicates that there was no significant preferred orientation in the palisade layer as a whole. Only in the surface layer was any preferred orientation detected, and here {1014} planes tended to lie parallel to the surface. The results are compared with previously published data, and calcite nucleation and growth are discussed.
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    European biophysics journal 7 (1981), S. 209-212 
    ISSN: 1432-1017
    Keywords: Photosynthetic bacteria ; Electron microscopy ; Planar lattices
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    Topics: Biology , Physics
    Notes: Abstract The thylakoids of Rhodopseudomonas viridis have been studied by freeze-fracturing whole cells. Depending on growth conditions and treatment before freezing, three different types of particle arrangements in the photosynthetic membrane are reported: a random arrangement, an isometric (quadratic) lattice arrangement with a lattice constant of 12.5 ± 0.8 nm, and a hexagonal lattice arrangement with a lattice constant of 12.5 ± 0.8 nm.
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  • 27
    ISSN: 1432-1041
    Keywords: sodium valproate ; epileptic patients ; pharmacokinetics ; plasma concentration ; prediction ; maintenance dosage
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Pharmacokinetic analysis of the plasma valproic acid concentration-time course, following a single oral dose (600 mg) of sodium valproate, was performed in 20 epileptic patients as an aid to the prediction of a proper chronic dosage regimen. A simple one-compartment model was found inadequate to describe the drug concentration-time course in 15 of the 20 patients studied. The average elimination (β phase) half-life of 9 h was shorter than that previously reported in healthy subjects. The latter observation and the wide variation in plasma valproic acid clearance observed between patients (0.09–0.53 ml/kg/min) may have been related to its altered disposition by concomitant anticonvulsant therapy. Sodium valproate maintenance therapy, determined by single-dose pharmacokinetic prediction of steady-state plasma valproic acid levels, did not require dosage adjustment because of unwanted effects. However, the occurrence of drug-related adverse events led to dosage reduction in 4 of 9 patients whose chronic therapy was not pharmacokinetically predicted. Moreover, the pharmacokinetic variability demonstrated for sodium valproate by patients on multiple therapy, whose chronic sodium valproate therapy was pharmacokinetically predicted, indicates the value of monitoring plasma valproic acid levels for the regulation of anticonvulsant therapy.
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  • 28
    ISSN: 1432-1041
    Keywords: prenalterol ; beta1-adrenoceptor agonist ; metabolic effects ; pharmacokinetics
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The metabolic and haemodynamic effects of three intravenous doses (0.5, 1.0 and 4.0 mg) of prenalterol, a selective β1-adrenoceptor agonist, were studied in 10 healthy male subjects. Plasma levels of prenalterol during the experiments were related to the haemodynamic effects. Prenalterol induced a dose-dependent increase in systolic blood pressure and heart rate. The maximal effects amounted to about 30 mm Hg and 15 beats/min, respectively, after the highest dose (4.0 mg). The diastolic blood pressure fell by a maximum of about 15 mm Hg. The effect of prenalterol on systolic blood pressure and heart rate persisted for about 3 h after the end of the last infusion, whereas that on diastolic blood pressure only lasted for 60 min. Compared with placebo, there was a moderate increase in plasma FFA and glycerol. A small rise in insulin level was also recorded, but no significant change was seen in other metabolic variables — triglycerides, glucose, lactate, pyruvate. Serum potassium tended to decrease and serum sodium was unchanged. The initial distribution of prenalterol was rapid (half-life 7 min) and the overall elimination rate corresponded to a plasma half-life of 2 h. A linear relationship was found between the plasma level of prenalterol and its effects on systolic blood pressure and heart rate.
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  • 29
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    European journal of clinical pharmacology 17 (1980), S. 111-116 
    ISSN: 1432-1041
    Keywords: zimelidine ; norzimelidine ; antidepressants ; pharmacokinetics ; bioavailability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The systemic availability of a new antidepressant, zimelidine, and of its pharmacologically active metabolite, norzimelidine, was studied in six healthy male volunteers. Three single doses of zimelidine (25 mg and 100 mg orally and 25 mg i.v.) and two single doses of norzimelidine (25 mg orally and i. v.) were given to each volunteer allowing at least seven days between administrations. Plasma concentrations of zimelidine and norzimelidine were determined in serial blood samples by HPLC. Following oral zimelidine peak plasma concentrations of the metabolite were attained about 3 h after dosing. Oral administration of norzimelidine itself resulted in a plasma concentration profile for this compound that was similar to that observed after oral zimelidine. Utilising the plasma concentration data following intravenous infusion of each compound, the elimination half-lives for zimelidine and norzimelidine were calculated to be 5.1 h (range 4.3–6.0) and 15.5 h (range 10.6–22.9) respectively. The total body clearances of the 2 compounds were similar at 0.52 l · min−1 (range 0.26–0.70) for zimelidine and 0.56 l · min−1 (range 0.28–0.83) for norzimelidine. The substantially longer elimination half-life of norzimelidine was apparently the result of a larger volume of distribution (9.4 l · kg−1; range 7.8–11.4) for this metabolite, as compared to zimelidine (3.21 · kg−1; range 1.6–4.9). The calculated bioavailability of zimelidine was 26% (range 9.1–39) after the 25 mg oral dose, and 29% (range 14–46) after the 100 mg dose. The bioavailability of norzimelidine was 66% (range 36–91). However, oral administration of zimelidine resulted in as much or more norzimelidine reaching the systemic circulation, as the oral administration of norzimelidine itself. This is important as a large part of the activity of the drug may be due to the metabolite.
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    European journal of clinical pharmacology 17 (1980), S. 129-133 
    ISSN: 1432-1041
    Keywords: dapsone ; salivary drug elimination ; pharmacokinetics ; acetylator phenotype
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary A high performance thin layer chromatographic assay for dapsone is described with a minimum level of detection of 20 ng ml−1 which is suitable for the study of dapsone pharmacokinetics in plasma and saliva. 100 mg dapsone was administered orally to seven normal adult volunteers, the mean plasma pharmacokinetic parameters were: α=0.23 h−1; β=0.0236 h−1, and t1/2β=30.2 h. Dapsone is also eliminated into the saliva and the t1/2 may be determined via its estimation in saliva. It is 73% bound to plasma protein and the saliva/plasma concentration ratio was found to be 27%. In two subjects the free plasma dapsone concentration was identical to the simultaneous salivary dapsone concentration. Therefore the salivary dapsone concentration is a measure of the free plasma fraction of dapsone. Saliva/plasma dapsone concentration ratios show no time or concentration dependence and little inter-individual variation but are unsuitable for acetylator phenotype determination because monoacetyldapsone is not eliminated in the saliva.
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  • 31
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    European journal of clinical pharmacology 18 (1980), S. 321-326 
    ISSN: 1432-1041
    Keywords: sotalol ; hypertension ; renal impairment ; chronic administration ; pharmacokinetics
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Ten hypertensive patients with moderate to severe impairment of renal function were treated with sotalol for 5 to 10 weeks (average 6.4 weeks). Dosage was individually titrated (range 80 to 480 mg daily). The drug was given once daily in the morning. In eight patients blood pressure was satisfactorily controlled. Higher steady-state levels were observed than have been reported after similar doses in patients with normal renal function. The apparent first-order elimination rate constant and plasma clearance were significantly correlated with glomerular filtration rate. For an anuric patient, serum half-life was calculated to be 69 h. In relation to the raised plasma levels, side effects were uncommon. Since sotalol is excreted predominantly via the kidney, therapy in patients with impaired renal function should start with a low dose and any increase in dosage should be made carefully. As the anti-hypertensive effect does not appear to be correlated with the plasma level or with tolerance, adjustment of dose should be based on clinical response.
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  • 32
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    European journal of clinical pharmacology 18 (1980), S. 517-520 
    ISSN: 1432-1041
    Keywords: desmethyldiazepam ; oxazepam ; cimetidine ; hepatic elimination ; pharmacokinetics ; interaction
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of single oral doses of desmethyldiazepam 20 mg or oxazepam 50 mg were studied in 5 healthy volunteers under controlled conditions, before and following a 24 h pretreatment with cimetidine 200 mg×5. Cimetidine significantly impaired (p=0.03) the elimination of desmethyldiazepam, as shown prolongation of its elimination half-life from 51.7±21.9 h to 72.6±39.4 h (mean ± SD), and a decrease in total plasma clearance from 12.0±2.7 ml/min to 8.6±3.3 ml/min. The disposition of oxazepam was not affected. From these results, and recently published data on diazepam and chlordiazepoxide, it is concluded that cimetidine impairs the hepatic elimination of those benzodiazepines which are metabolized by phase I reactions.
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  • 33
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    European journal of clinical pharmacology 19 (1981), S. 263-269 
    ISSN: 1432-1041
    Keywords: chlormethiazole ; pharmacokinetics ; pharmacodynamics ; sedatives ; blood concentrations ; amnesia
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Chlormethiazole ethanedisulphonate (0.8%) (Hemineurin, Astra) was administered to 10 healthy unpremedicated volunteers at a constant-rate infusion of 2.5 ml/min for 60 min (Phase 1, n=5) and 113 min (Phase 2, n=5). With one exception, chlormethiazole blood concentration-time data were described by a two-compartment open model. Total body clearance was the same in both phases (1.15 l · min−1, SD 0.49; and 1.05 l · min−1, SD 0.36 respectively) and was similar to the clearance of indocyanine green. No correlation was found between clearance, initial dilution volume (137 l, SD 62; and 125 l, SD 33 in 1 and 2 phases respectively) or volume of distribution at steady-state equilibrium (308 l, SD 91; and 224 l, SD 59) with either body weight or estimated lean tissue mass. Slow half-life was 289 min (SD 169) in Phase 1 and 253 min (SD 172) in Phase 2. Moderately heavy sedation associated with amnesia while retaining the ability to readily obey verbal commands was achieved in one subject of Phase 1 and 4 subjects of Phase 2 and occurred at a mean chlormethiazole ethanedisulphonate blood concentration of 9.2 mg · l−1 (SD 2.9). Transient nasal irritation was experienced by all subjects during the initial stages of infusion. A rise in pulse rate (33%, SD 8) was a prominent feature but blood pressure and respiratory rates were very stable.
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  • 34
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    European journal of clinical pharmacology 17 (1980), S. 449-457 
    ISSN: 1432-1041
    Keywords: alcuronium ; single dose ; multiple dose ; plasma levels ; neuromuscular response ; pharmacokinetics ; anaesthesia
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetic behaviour of alcuronium is described for nineteen patients undergoing anaesthesia for elective surgery. Eleven patients received a single bolus intravenous dose of 0.25 mg/kg, while 8 patients required additional doses of 0.125 mg/kg. A two-compartment open model was found to describe adequately both the single dose and multiple dose data for the majority of patients. No significant differences were found in the model-independent pharmacokinetic parameters between the single and multiple dose studies. Mean values for the pooled data for the half-life (t1/2β), apparent volume of distribution (Vdβ), volume of distribution at steady-state (Vdss), volume of the central compartment (Vc) and plasma clearance (Clp) were 198.75 min, 24.261, 20.891, 8.181 and 90.22 ml/min respectively. Evoked muscle twitch response was monitored in 17 of the patients to assess the degree of relaxant blockade. The bolus dose of alcuronium produced complete block in 9 patients and between 95 and 99% block in the remainder. The time of onset to maximum block ranged from 3 to 30 min with the concurrently measured plasma levels of alcuronium being 0.79 to 2.25 µg/ml. The time taken following bolus administration to 5% recovery (95% paralysis) was a mean of 42 min and the corresponding mean alcuronium plasma concentration was 0.78 µg/ml.
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  • 35
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    European journal of clinical pharmacology 18 (1980), S. 269-273 
    ISSN: 1432-1041
    Keywords: paracetamol ; thyrotoxicosis ; hypothyroidism ; drug disposition ; pharmacokinetics
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The absorption, distribution and elimination of oral paracetamol have been studied in patients before and after treatment of thyrotoxicosis (n=7) and hypothyroidism (n=4). Absorption was faster in patients with untreated thyrotoxicosis than when subsequently euthyroid. The peak paracetamol concentration, however, was lower in thyrotoxic patients due to an apparent increase in the total body clearance and a shorter plasma half-life. Both absorption and elimination rates were reduced in hypothyroid patients, but were not significantly different from the euthyroid results. When estimated using a two compartment model the total volume of distribution and the hybrid distribution rate constants were unrelated to thyroid status, but the apparent volume of the central compartment was significantly greater in the thyrotoxic group. These changes in drug disposition may contribute to differences in drug response seen in thyroid disease.
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  • 36
    ISSN: 1432-1041
    Keywords: alminoprofene ; antalgic ; pharmacokinetics ; single dose ; multiple doses
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    Notes: Summary 2-(p-methylallylaminophenyl) propionic acid, alminoprofene (INN), a new antalgic drug, was administered orally to men as a single (300 mg) and multiple doses (300 mg three times daily). Plasma and urine concentrations of alminoprofene were determined by gas-liquid chromatography. After the single oral dose, the peak plasma level (36.2 to 41.5 mg/l) was reached within 0.5–1.5 h. The biological half-life ranged from 2.5 to 3.2 h. During chronic administration of alminoprofene, steady-state equilibrium quilibrium was etablished within 24 h. The urinary excretion of alminoprofene as unchanged product and as glucuronide was very important.
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  • 37
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    European journal of clinical pharmacology 18 (1980), S. 423-428 
    ISSN: 1432-1041
    Keywords: pyridostigmine ; myasthenia gravis ; pharmacokinetics ; bioavailability ; plasma levels
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of pyridostigmine was evaluated after intravenous injection in two healthy male volunteers and after oral administration to five subjects. Plasma concentrations of pyridostigmine were determined after ion pair extraction from plasma and analysis by gas chromatography — mass spectrometry with chemical ionization, using d6-pyridostigmine as internal standard. Degradation of pyridostigmine in vitro was compensated for by use of the deuterated internal standard and by rapid cooling and separation of plasma after blood sampling. After intravenous administration of pyridostigmine 2.5 mg the plasma elimination half-life was 1.52 h, the volume of distribution was 1.43 l/kg and the plasma clearance 0.65 l/kg × h. The pharmacokinetic constants were very similar after oral administration of pyridostigmine 120 mg; the elimination half-life was 1.78±0.24 h, the volume of distribution 1.64±0.29 l/kg and the plasma clearance was 0.66±0.22 l/kg × h. The bioavailability was calculated to be 7.6±2.4%. When pyridostigmine was taken together with food, the time to reach the peak plasma concentration was prolonged from 1.7 to 3.2 h. Bioavailability, however, was not influenced by concomitant food intake. “Steady-state” plasma concentrations of pyridostigmine were measured in myasthenic patients on their ordinary dose schedule of cholinesterase inhibitor drugs. More than a seven-fold difference in steady-state plasma concentration was found between patients taking approximately the same daily dose of pyridostigmine.
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  • 38
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    European journal of clinical pharmacology 18 (1980), S. 473-477 
    ISSN: 1432-1041
    Keywords: aminophylline ; asthma ; serum theophylline ; pharmacokinetics ; prediction of serum level
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In 15 acutely ill asthmatics the steady-state serum theophylline concentration was predicted by the method of Chiou et al. using two serum concentration measurements obtained 1 and 5h after starting a continuous infusion of aminophylline. Two theophylline assays with different precision characteristics were compared. With a precise HPLC-assay the prediction was excellent: prediction error (predicted minus measured concentration)=−0.22±1.97 mg/l (mean ± SD); r=0.922. When the theophylline concentration was determined by a rapid enzyme immunoassay of lower precision, but convenient for clinical use, the prediction was less accurate (prediction error=0.58±3.88, r=0.852). However, it was still clearly superior to dosing recommendations based on the population average of theophylline clearance, even after taking into consideration the effect of smoking, congestive heart failure and cirrhosis (prediction error=3.62±13.36, r=0.560). As employed in this study, the method may be useful in helping the physician to choose the optimal dose in severely ill asthmatics.
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  • 39
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    European journal of clinical pharmacology 17 (1980), S. 459-463 
    ISSN: 1432-1041
    Keywords: colestipol ; fenofibrate ; fenofibric acid ; pharmacokinetics ; interaction ; volunteers
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The possibility of a pharmacokinetic interaction between two hypolipidemic drugs, colestipol, an ion exchange resin, and fenofibrate, a phenoxyacid derivative, was studied in 6 male volunteers. The investigation followed a four-step protocol during 18 days, and relied on determination of plasma and urinary levels of fenofibric acid, the active metabolite of fenofibrate. The kinetics of a single dose of fenofibrate 300 mg was established over 3 days. Thereafter, from Days 4 to 9 fenofibrate was given daily as 200 mg in the morning and 100 mg in the evening; the plasma fenofibric acid level reached about 10 µg/ml. From Days 9 to 15 the same dose of fenofibrate was administered together with colestipol 10 g in the morning and 5 g in the evening. Plasma fenofibric acid concentrations remained unchanged and the 24 h urinary excretion of fenofibric acid did not fall. On Day 15, a last single dose of fenofibrate 300 mg was given with colestipol 15 g. The pharmacokinetic pattern of fenofibric acid on Days 15 to 18 did not differ significantly from that found previously (Days 1 to 3). From these results, it is likely that there is no pharmacokinetic interaction between the two hypolipidemic drugs.
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  • 40
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    European journal of clinical pharmacology 18 (1980), S. 51-53 
    ISSN: 1432-1041
    Keywords: pethidine ; phenobarbital ; aminoglycoside antibiotics ; pharmacokinetics ; clinical response
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  • 41
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    European journal of clinical pharmacology 18 (1980), S. 55-63 
    ISSN: 1432-1041
    Keywords: diuretics ; furosemide ; caffeine ; theophylline ; neonate ; pharmacokinetics ; disposition
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The elimination of diuretics and methylxanthines is considerably slower in the neonate than in the adult. Dose guidelines, especially during long term maintenance, must be adjusted to account for this slower drug elimination. Pharmacokinetic studies and the requisite pharmacologic evaluation on diuretics such as hydrochlorothiazide, spironolactone, ethacrynic acid and others should be done. Furosemide undergoes biotransformation in the newborn producing an acid metabolite and a glucuronide conjugate. Methylxanthines are effective in the treatment of neonatal apnea. Plasma elimination of theophylline is exceedingly slow, more so with caffeine. Decreased elimination is partly explained by decreased oxidative biotransformation. Caffeine is excreted in the urine of the newborn mainly unchanged (85%) in contrast to the adult where caffeine is a minor portion of urinary excretion (2%). Theophylline is methylated to caffeine and may possibly exert additive pharmacologic effects.
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  • 42
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    European journal of clinical pharmacology 18 (1980), S. 195-198 
    ISSN: 1432-1041
    Keywords: ampicillin ; age ; oral dose ; i. v. dose ; pharmacokinetics
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Ampicillin (500 mg) was administered intravenously (i. v.) and orally to a small panel of young and elderly subjects in a cross-over fashion. Plasma concentrations of ampicillin were measured by a fluorimetric technique for 8 h following dosage. A two compartment-open model was used to characterise the plasma concentration-time data for the intravenous study, and a one compartment-open model incorporating an absorption lag time and a first-order absorption rate constant for the oral data. Plasma clearance after i. v. ampicillin was found to be significantly decreased in the elderly (P〈0.05, 0.08 1 h−1kg−1 versus 0.18 1 h−1kg−1), and half life and area under the plasma level-time curve were significantly increased (P〈0.05, 6.70 h versus 1.68 h, t1/2β; p〈0.01, 176.51 µg·h ml−1 versus 37.88 µg·h ml−1, AUC o ∞ ) as compared to the young. No sigificant differences were observed between the age groups for the volume of distribution terms and the changes in drug handling noted in the elderly were attributed to a decrease in the renal elimination of ampicillin. Following oral administration a significant increase in t1/2β, AUC o ∞ and the maximum plasma concentration (Cpmax P〈0.01, 6.59 µg ml−1 versus 3.42 µg ml−1) of ampicillin was found in the elderly subjects. These findings were similarly attributed to a decrease in drug elimination in the aged, since no apparent age differences were noted in the pharmacokinetic parameters governing both rate and extent of ampicillin absorption.
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  • 43
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    European journal of clinical pharmacology 18 (1980), S. 237-244 
    ISSN: 1432-1041
    Keywords: isosorbide dinitrate ; 2-isosorbide mononitrate ; 5-isosorbide mononitrate ; digital plethysmography ; hypotension ; bradycardia ; pharmacokinetics
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary 18 subjects were given isosorbide dinitrate (ISDN) 5 mg sublingually and serum concentrations of ISDN, 2-isosorbide mononitrate (2-ISMN) and 5-isosorbide mononitrate (5-ISMN) were measured, as well as changes in digital plethysmographic amplitude, heart rate, ECG, blood pressure and Schellong's test. ISDN was rapidly absorbed and metabolized, having an elimination half-life of 29 min. Its metabolites 2-ISMN and 5-ISMN had longer half-lives of 1.75 and 7.6 h respectively. The amplitude of the α-wave of the digital plethysmograph did not change significantly either in the predrug period or after placebo administration. It increased within 4 min of administration of ISDN, and reached a maximum after 14 min; the effect lasted for about 2 h. ISDN lowers blood pressure and increases heart rate in most volunteers, but in 3 of the 18 subjects severe hypotension occurred, accompanied by severe, reversible bradycardia, which was probably due to vagal reflexes initiated by the markedly diminished ventricular enddiastolic volume (LVEDV) and pressure (LVEDP). No correlation could be demonstrated between the serum concentration of ISDN and/or its vasoactive metabolites and changes in plethysmographic amplitude.
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  • 44
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    European journal of clinical pharmacology 21 (1982), S. 287-291 
    ISSN: 1432-1041
    Keywords: tolmesoxide ; hypertension ; pharmacokinetics
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Tolmesoxide is a new, direct-acting vasodilator drug for use in the management of both hypertension and cardiac failure. In 6 essential hypertensives inadequately controlled by combined β-blocker and diuretic therapy (average supine blood pressure 178/103 mm Hg) the addition of tolmesoxide (300–900 mg daily) was associated with a significant improvement in blood pressure control (average supine blood pressure 161/89 mmHg). The effect of food on the pharmacokinetics and pharmacodynamics of tolmesoxide have also been studied because, particularly at higher doses, the drug has been associated with upper gastrointestinal upset and it has been empirically recommended that it be taken with food. The blood pressure and heart rate responses were not significantly different when tolmesoxide was taken fasting or with food. Food resulted in a significant reduction in the peak plasma tolmesoxide concentration (2.14 µg/ml compared to 2.97 µg/ml) and a significant increase in the time to reach peak plasma concentration (1.67 h compared to 0.63 h). Although there was no impairment of its hypotensive effect, food significantly altered the pharmacokinetics of tolmesoxide and may therefore be useful in reducing the gastrointestinal disturbance associated with its use. In the treatment of inadequately controlled hypertension, tolmesoxide has a limited role as an alternative vasodilator.
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  • 45
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    European journal of clinical pharmacology 21 (1982), S. 307-310 
    ISSN: 1432-1041
    Keywords: piretanide ; renal failure ; high dose ; pharmacokinetics
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The kinetics of piretanide was studied in patients with renal failure. After oral administration of a high dose of piretanide (96 mg), the pharmacokinetic parameters were: elimination rate constant 0.346±0.072 h−1, half life 2.00±0.35 h, and total plasma clearance 119.55±35.90 ml · min−1. Compared to the values obtained in adults with normal renal function, these results show a decrease in total plasma clearance, but conservation of the metabolic clearance which amounts to 45% of the total clearance in the healthy adult.
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  • 46
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    European journal of clinical pharmacology 21 (1982), S. 397-402 
    ISSN: 1432-1041
    Keywords: ergotamine ; migraine ; radioimmunoassay ; clinical effects ; adverse effects ; pharmacokinetics
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The systemic availability of ergotamine after a single therapeutic oral or rectal dose was studied using a radioimmunoassay during the headachefree state in 24 patients suffering from migraine. Plasma concentrations of the drug were compared with anamnestic data about its clinical effects in the same patients. Among 12 patients with a good therapeutic response to medication, the mean plasma ergotamine levels stayed in the range 0.20 to 0.50 ng/ml for 6h. Their mean plasma levels at 30 min (0.33ng/ml) and 1h (0.40ng/ml) were significantly higher than those (0.06 and 0.08ng/ml, respectively) in 9 patients with only a moderate therapeutic response. In 9 patients with a moderate and 3 with a poor therapeutic response, the mean plasma level generally stayed below 0.10ng/ml. The mean peak concentrations in moderate (0.13 ng/ml) and poor (0.11ng/ml) responders appeared later (at 3h) than in good responders (at 1h). Side effects of the medication appeared to be associated with relatively low plasma levels of ergotamine and also with delayed maximum plasma concentrations of the drug. The present results suggest that the time of the maximum plasma drug level is an important determinant of the clinical effects of ergotamine, and that a good therapeutic response may be expected if a plasma ergotamine level of 0.20ng/ml or more is achieved within 1 hour after oral or rectal administration.
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  • 47
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    European journal of clinical pharmacology 21 (1982), S. 343-350 
    ISSN: 1432-1041
    Keywords: orphenadrine ; single dose ; multiple doses ; bioavailability ; pharmacokinetics ; N-demethylorphenadrine ; metabolism ; dog ; man
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Plasma concentrations of orphenadrine were measured by a specific gaschromatographic method in 5 healthy male volunteers after a single oral dose of orphenadrine hydrochloride 100mg. The single dose pharmacokinetic profile of orphenadrine was evaluated from these data. The elimination half-life ranged from 13.2–20.1 h after the commercial tablet formulation. Plasma concentrations, determined in volunteers and patients under different conditions of repeated oral administration of the same formulation of orphenadrine hydrochloride exceeded the theoretical values, predicted from the single dose pharmacokinetics, by a factor 2 to 3. The elimination half-lives after discontinuation of treatment showed a 2 to 3-fold increase over the single dose values. This demonstrates a clear discrepancy between the multiple and single dose pharmacokinetics of orphenadrine. Experiments in dogs suggested competition for biotransformation between orphenadrine and its metabolite N-demethylorphenadrine. Product inhibition of this type could explain the observed discrepancy.
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  • 48
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    European journal of clinical pharmacology 22 (1982), S. 273-279 
    ISSN: 1432-1041
    Keywords: amoxycillin ; i.v. administration ; pharmacokinetics ; two- and three-compartment models
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetic characteristics of amoxycillin were studied in healthy volunteers after intravenous injection of 250 mg, 500 mg and 1,000 mg, and infusion of 2 g and 5 g. Serum concentrations were fitted using either bi- and tri- exponentional equations. Comparison of the regression curves obtained revealed that the three-compartment model gave a better fit to the serum concentration versus time curve. It was evident that there was a third, slow, dose dependent phase of disposition. This result has been confirmed by the fact that the terminal half life of amoxycillin on cessation of a continuous infusion is significantly greater than after acute administration.
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  • 49
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    Keywords: indapamide ; bioavailability ; pharmacokinetics
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Two formulations of indapamide tablets (2.5 mg) were given as a 5.0 mg dose and the subsequent blood levels were compared to those obtained after administration of a 5.0 mg solution. The study was conducted as a randomized three-way crossover design using healthy male volunteers. The drug was well tolerated by all the subjects involved. The area under the blood concentration versus time curve, extrapolated to infinity was essentially the same for all three formulations (4.2, 4.7, and 4.4 µg-h/ml). Statistical comparison of the blood levels from the two tablets showed that one tablet had a significantly greater maximum blood concentration (263 vs 231 ng/ml) and a significantly shorter time of maximum blood concentration (2.3 vs 3.5 h). Cmax (333 ng/ml) and tmax (0.7 h) values for the solution were significantly higher than either tablet. The average half-life (β-phase) for all three formulations was 15 h, while the average systemic clearance was 20 ml/min. Indapamide has a low clearance rate and there was no evidence that the drug undergoes a first-pass effect.
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  • 50
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    European journal of clinical pharmacology 22 (1982), S. 257-264 
    ISSN: 1432-1041
    Keywords: TRIS buffer ; metabolic acidosis ; pharmacokinetics ; cellular uptake ; renal excretion ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary To investigate the pharmacokinetics of TRIS, an infusion of the buffer was given to 6 healthy volunteers (121 mg/kg=1 mmol/kg; pH 7.4) and to 20 patients suffering from metabolic acidosis (109–376 mg/kg; pH 10.9). The drug exhibited two-compartment characteristics in volunteers (t0.5,β=5.6 h) and patients with intact renal function (t0.5,β=16.3–45.6 h). The final volume of distribution (Vβ) indicated uptake into tissues, but equilibration between body compartments was slow. Mainly unchanged TRIS was eliminated by the kidney; 82% of the administered dose was recovered from 24 h-urine of healthy subjects. In the patients a linear correlation between creatinine-clearance and TRIS-clearance was observed, the latter always being somewhat greater than the former. Only insignificant amounts of the drug were found in bile and gastric juice. In anuric patients the plasma concentration of TRIS declined monoexponentially, with a half-life between 10 and 58 h. Haemodialysis or haemofiltration did not influence this process. From the data it seems questionable whether cellular uptake of TRIS is an important factor in the therapy of intracellular acidosis, but the possibility of drug accumulation must be borne in mind if repeated doses are given to the same patient.
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  • 51
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    European journal of clinical pharmacology 20 (1981), S. 147-155 
    ISSN: 1432-1041
    Keywords: azapropazone ; cirrhosis ; renal failure ; non-steroidal anti-inflammatory drug ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The disposition of azapropazone 600 mg i.v. was investigated in 6 healthy subjects, 13 patients with cirrhosis and 8 patients with renal failure. In healthy subjects the elimination half-life was 12.2±2.1 h (mean ± SD), the volume of distribution 10.6±3.31 and the total clearance was 597±135 ml·h−1. Renal clearance accounted for about 62% of the total clearance. The free fraction of azapropazone in the plasma was 0.0045±0.0006. The patients with cirrhosis were divided into Group I with modest and Group II with severe impairment of liver function. In Group I the total clearance of azapropazone was not significantly different from that in healthy subjects. There was a 2.5-fold increase in its free fraction in plasma, and a reduction in the free drug clearance to about half that in healthy subjects. In Group II patients total clearance was reduced to about 20% of normal. This was partly due to reduced non-renal clearance but mainly to impaired renal clearance of azapropazone. The diminished renal clearance was considered at least in part to represent a drug-induced impairment of renal function, as there was a concomitant reduction in creatinine clearance. The free fraction of azapropazone in the plasma was markedly enhanced (〉0.02), and simultaneously, free drug clearance was drastically reduced, to about 2% of that in healthy subjects. In patients with renal failure the total clearance was diminished, depending on the degree of impairment of kidney function. Anephric patients were estimated to have about one third of the total clearance in normal subjects. The free fraction of azapropazone in the plasma was increased in 4 of the 8 patients. It is concluded that patients with cirrhosis and modest impairment of liver function may require about half the normal dose of azapropazone, since free drug clearance is reduced by about 50%. Patients with severe impairment of liver function are expected to be highly susceptible to dose-related side effects, since the pronounced increase in the free fraction in plasma and the decreases in renal and non-renal clearance lead to marked reduction in free drug clearance and so to accumulation of free drug in the body. In patients with renal failure the dose of azapropazone should be reduced according to the degree of impairment of kidney function and plasma protein binding of the drug.
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  • 52
    ISSN: 1432-1041
    Keywords: pindolol ; beta-blockade ; slow release tablet ; plasma levels ; urinary excretion ; pharmacokinetics ; pharmacodynamics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In 10 healthy volunteers the time course of cardiac beta-adrenoceptor blocking activity, plasma levels and cumulative urinary excretion of pindolol were compared during a 4-day course of pindolol 5 mg (Visken®) t. d. s., and one tablet of pindolol 20 mg retard (Visken® retard) once a day. After oral administration of the 20 mg retard tablet, plasma concentrations of pindolol higher than half the maximum value (1/2 Cp (tmax)) were maintained about 2.5 times as long as after administration of the conventional 5 mg tablet. This is evidence for an important and marked retardation of drug release. During treatment with pindolol 20 mg retard once daily, cardiac beta-adrenoceptor blockade, measured by the reduction in exercise-induced tachycardia and in the exercise-induced rise in systolic blood pressure, at almost all times throughout the 24 h period was at least as great as during treatment with pindolol 5 mg t. d. s. This suggests that patients successfully treated with pindolol 5 mg t. d. s. can be maintained with the same beta-adrenoceptor blockade by a single tablet of pindolol 20 mg retard once daily.
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  • 53
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    European journal of clinical pharmacology 23 (1982), S. 75-80 
    ISSN: 1432-1041
    Keywords: psoriasis ; 8-methoxypsoralen ; food influence ; suction blister fluid ; serum ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The influence of food on the kinetics of 8-methoxypsoralen (8-MOP) in serum and suction blister fluid was evaluated in a cross-over study in 19 psoriatic patients under PUVA treatment. The peak serum concentration of 8-MOP was reached 1.5 h after ingestion on an empty stomach, and in suction blister fluid the maximum concentration was already present in the first sample taken after 2 h, the time when UVA radiation was given. The postprandial kinetics of 8-MOP in serum and suction blister fluid differed, the highest levels being reached, respectively, at 2.4 and 3 h after intake, i.e. in both body fluids after irradiation had started. The side effects of 8-MOP, such as nausea and dizziness, in the two groups were similar. The present results indicate that to optimize the therapeutic effect of PUVA in individual patients, 8-MOP should be given on an empty stomach.
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  • 54
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    European journal of clinical pharmacology 23 (1982), S. 189-195 
    ISSN: 1432-1041
    Keywords: befunolol ; propranolol ; pharmacokinetics ; pharmacodynamic effects ; beta-adrenoceptor blocking agent
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Repeated doses of a new β-adrenoceptor blocking agent, befunolol, were administered orally to adult male volunteers for a cross-over comparison with propranolol. The β-adrenoceptor blocking activity of befunolol was greater than that of propranolol when assessed by the percentage reduction in exercise-induced tachycardia. The elimination half-life of drug was significantly prolonged on repeated administration of propranolol, but not of befunolol. The percentage reduction in exercise-induced tachycardia was highly correlated with the log plasma level of each drug. Both drugs produced a significant reduction in pre-exercise systolic and diastolic blood pressure, and significant attenuation of exercise-induced rise in systolic blood pressure.
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  • 55
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    European journal of clinical pharmacology 23 (1982), S. 235-240 
    ISSN: 1432-1041
    Keywords: ergotamine ; pharmacokinetics ; migraine ; plasma drug levels ; i.v. administration ; i.m. administration ; bioavailability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The kinetics of ergotamine has been investigated in migrainous patients using a new, specific, sensitive HPLC assay (detection limit 100 pg/ml plasma). 10 patients were given ergotamine tartrate 0.5 mg i.v. and 5 of them received the same dose i.m. 2–3 weeks later. Blood samples were collected for up to 54 h following administration and the plasma concentration were analysed. After intravenous administration the plasma ergotamine declined rapidly, with an initial distribution half-life of 3 min followed by a mean terminal half-life of 1.86 h (range 90–155 min). The mean total plasma clearance was 11.0 ml kg−1 min−1, and the volume of distribution (Vdβ ) was 1847.6 ml kg−1. Individual t1/2β showed a positive linear correlation with the individual Vdβ . The intramuscular absorption of ergotamine was rapid and maximum plasma levels were usually obtained 10 min following administration. The biological availability was incomplete and variable at 46.6% (range 28.3–60.8%).
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  • 56
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    European journal of clinical pharmacology 23 (1982), S. 327-330 
    ISSN: 1432-1041
    Keywords: bendroflumethiazide ; cantharides plasters ; blister fluid ; plasma levels ; pharmacokinetics ; compartmental analysis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of bendroflumethiazide (BFT) was investigated following the oral administration of 10 mg to 3 healthy volunteers. Each subject participated twice in the study. BFT was determined in plasma and cantharides blister fluid from 1/2 to 30 h post administration. Blister fluid was obtained from blisters 10–22 h old. Plasma levels were fitted to a tri-exponential equation and the concentration of the drug in the peripheral compartment was calculated from the microscopic rate constants. In 5 of 6 cases investigated, cantharides blister fluid levels paralleled the concentration of the drug in the peripheral compartment. The mean blister fluid levels exceeded the calculated concentration in Compartment 2 1.46 fold. In one case, the blister fluid level paralleled the plasma level. This subject clearly differed from the others as more than 10 h were required for blister formation in her. The results suggest that following the administration of BFT, cantharides blister fluid behaves as part of the peripheral compartment. The possible value of studying blister fluid levels in pharmacokinetic investigations is discussed.
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  • 57
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    European journal of clinical pharmacology 23 (1982), S. 343-347 
    ISSN: 1432-1041
    Keywords: valproic acid ; fatty acids ; plasma protein binding ; pharmacokinetics ; drug metabolism
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effect of physiologic variations of free fatty acid levels on in vivo valproic acid plasma protein binding was studied in 6 healthy adult subjects. 14 blood samples were taken during a 12-h dosing interval at steady state while in a fed condition and also during a 27 h fast. Free fraction and total valproate concentration were determined by equilibrium dialysis and GLC, respectively. Free fatty acid levels were determined from both fresh samples and samples incubated at 37°C for 12 h, the latter in order to simulate equilibrium dialysis conditions. Fasting resulted in increased serum free fatty acid levels in all subjects, ranging from 34–182% (p〈0.01). Incubation also caused free fatty acid levels to rise, more so in fed samples (50–87%,p〈0.01) than in fasting samples (10–50%,p〈0.01). Fasting resulted in a 9% increase in the mean free fraction for all subjects combined (p〈0.01). Regression analysis of 180 sets of values for free fraction, total valproate concentration and free fatty acid level suggested that valproate concentration accounts for 17% and free fatty acid level for 37% of the variation in free fraction. Mean clearance was unchanged by fasting despite an increased free fraction suggesting decreased intrinsic clearance (i.e. decreased metabolism) of valproate under these conditions.
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  • 58
    ISSN: 1432-1041
    Keywords: L-threo-3,4-dihydroxyphenylserine ; familial amyloid polyneuropathy ; pharmacokinetics ; norepinephrine ; pressor response
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of oralL-threo-3,4-dihydroxyphenylserine (L-threo-DOPS) was studied in 7 normal subjects and 7 patients with familial amyloid polyneuropathy. Each person swallowed a single 300 mg dose in the fasting state, andL-threo-DOPS in plasma and urine was determined by high performance liquid chromatography with an electrochemical detector after separation on a boric acid gel column.L-threo-DOPS was slowly absorbed by normal subjects; the maximum plasma concentration occurred 3 h after administration and 20% of the oral dose was recovered unchanged in the urine within 12 h. It induced a substantial elevation of plasma norepinephrine levels, the peak being attained at 5 h, but without any change in blood pressure. In the patients, the absorption and metabolism ofL-threo-DOPS were delayed, and a prolonged pressor response was observed, with a peak after 8 h. It was concluded that the effects on plasma norepinephrine and blood pressure of oralL-threo-DOPS were essentially equal to those of twice as large a dose ofDl-threo-DOPS.
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  • 59
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    European journal of clinical pharmacology 23 (1982), S. 501-504 
    ISSN: 1432-1041
    Keywords: cimetidine ; uraemia ; dosing regimen ; prediction ; computer program ; old age ; pharmacokinetics
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Using a recently developed computer program based on a correlation between methods to predict the elimination half-life and apparent volume of distribution of cimetidine and actual data from patients, ideal dosage regimens were generated for patients with renal impairment and for geriatric patients, together with the corresponding maximum and minimum steady state concentrations. Using the ideal dosage regimens, practical regimens with feasible dosing intervals of 6, 8 and 12 h were computed, which should result in therapeutic concentrations of 0.4 to 1.3 µg/ml. For uraemic patients and geriatric patients above the age of 75 years it would be desirable to have an additional oral 100 mg dosage form.
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  • 60
    ISSN: 1432-1041
    Keywords: amitriptyline ; imipramine ; clomipramine ; antidepressant overdose ; clinical effects ; pharmacokinetics ; cardiotoxicity ; maprotiline ; doxepine ; nortriptyline ; opipramol
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Twenty-nine cases of self-poisoning with antidepressants (amitriptyline, imipramine, clomipramine, maprotiline, doxepine, nortriptyline, opipramol) were examined by frequent observation of CNS effects, heart rate, blood pressure and standard ECG, 24 h-ECG-monitoring, measurement of systolic time intervals, EEG recordings and frequent measurement of serum levels of antidepressants and primary metabolites. None of the patients died. Maximum total serum antidepressant level (parent compound + desmethyl metabolite) ranged from 20 to 2200 µg/l, with concentrations above 500 µg/l in 11 cases. The serum amitriptyline concentration remained high for 3–4 days in some of the severely intoxicated patients and the decay curves were compatible with partly saturated elimination. A degree of unconsciousness and the occurrence of excitation and hallucinations were generally seen in cases with total serum antidepressant levels above 500 µg/l. Grand mal seizures occurred more frequently at high antidepressant levels, but could not be predicted from the EEG recordings. Increased heart rate and prolonged QRS- and QTc-intervals were significantly correlated with the total serum antidpressant level. 24 h-ECG-monitoring revealed no serious arrhythmias or instances of heart block. Hypotension was only seen initially in few patients. Systolic time interval measurements showed changes suggesting impaired myocardial performance (elevated PEP/LVET ratio) at intermediate (60–500 µg/l) but not high (〉500 µg/l) total serum antidepressant levels. Measurement of serum concentration in antidepressant intoxication is important for identification of patients with high serum levels and the corresponding risk of developing toxic reactions, and to exclude patients with a low concentration who do not require intensive observation.
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  • 61
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    European journal of clinical pharmacology 24 (1983), S. 185-190 
    ISSN: 1432-1041
    Keywords: amezinium ; hypotension ; antihypotensive drug ; ECG ; concentration-effect relationship ; pharmacokinetics
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Blood pressure, ECG and plasma concentration were determined for up to 12h following single i.v. (10 mg) and oral (20 mg) doses of amezinium (Regulton®) in 8 healthy, male volunteers. The i.v. and oral doses were almost equi-active in significantly increasing systolic blood pressure (SBP) by 14.5 and 15.6 mmHg, respectively. The maximum SBP after the i.v. dose was reached after 45 min, and 105 min after oral administration. The heart rate fell reflexly. The increases in mean and diastolic blood pressures were not significant. Pulse pressure was enhanced after both i.v. and oral administration. The effect on systolic blood pressure lasted for about 4 h. There was a slight shortening of the QTc duration, which could not be explained as a drug effect. Other ECG time intervals were not altered. Multiple regression analysis showed a significant positive correlation between the log plasma concentration and the increase in SBP between 0.5 and 5 h after oral administration (r=0.78,p〈0.001) and between 0.75 and 5 h after i.v. administration (r=0.83,p〈0.001). 30 min after amezinium p.o. the mean SBP began to rise, when a plasma level of about 30 ng/ml was reached.
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  • 62
    ISSN: 1432-1041
    Keywords: sulfinpyrazone ; pharmacokinetics ; metabolites ; inhibition of platelet aggregation
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of sulfinpyrazone, and the plasma levels of its sulfide and sulfone metabolites, have been determined after a single oral dose (400 mg) and during steady-state conditions (4×200 mg daily for 6 days) in healthy female volunteers. The plasma half-lives of sulfinpyrazone, the sulfone and the sulfide were 3.7, 3.2 and 14.7 h, respectively, during steady-state. After a single dose and during steady state conditions the half-lives of sulfinpyrazone and the sulfone did not differ significantly. The trough plasma levels of the sulfide metabolite exceeded those of the parent compound in four of the six volunteers on the last day of the study. The data suggest that in man the most likely candidate for the prolonged inhibition of platelet aggregation observed after treatment with sulfinpyrazone is its sulfide metabolite, because of its prolonged elimination.
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  • 63
    ISSN: 1432-1041
    Keywords: trimethoprim ; sulphadiazine ; urinary tract infection ; children ; pharmacokinetics ; urinary concentrations
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The clinical effect and pharmacokinetics of the combination trimethoprim (TMP)-sulphadiazine (SD) were studied in 18 children with acute urinary tract infections (UTI), aged 2–56 months. A suspension of TMP-SD (9+41 mg/ml) was taken orally twice daily for 10 days. Various doses of TMP (2.9–3.7 mg/kg/day) and SD (12.9–16.7 mg/kg/day) were also given to children of different ages. After 2–4 days of treatment, bacterial cultures of urine were negative and C-reactive protein in serum, WBC count and ESR in all patients had become normal. Steady state serum levels for both components were reached after 4 or more days of treatment. At steady state, mean peak serum concentrations of TMP and SD of 1.4 µg/ml and 27 µg/ml, respectively, were found within 2–4 h after a fasting morning dose. The biological half-lives of TMP and SD were of the same order of magnitude, but the total clearance of TMP was 5 times greater than that of SD. The concentrations of TMP-SD in urine were invariably more than 10 times the minimum inhibitory concentrations (MIC) for the causative organisms (tested at the ratios 1:20 and 1:4 of TMP and SD). Non-metabolized SD constituted 77% of total SD in urine of infants, and 55% of total SD in children of 1 year or more. The TMP-SD combination showed a satisfactory clinical effect and favourable pharmacokinetic properties in children with UTI.
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  • 64
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    European journal of clinical pharmacology 24 (1983), S. 337-343 
    ISSN: 1432-1041
    Keywords: ketamine ; diazepam ; drug interaction ; pharmacokinetics ; premedication ; clorazepate ; drug metabolism ; enzyme induction
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Anaesthesia with continuous i.v. ketamine and 65% nitrous oxide in oxygen was given to a total of 49 patients undergoing major abdominal surgery. A control group was premedicated with atropine and other groups received in addition rectal diazepam or clorazepate i.v. Four further patients had been on oral diazepam or barbiturates for 1–14 years; as premedication they received atropine alone. The anaesthetic technique gave good operative conditions in the 4 groups of patients. The haemodynamic stimulation of ketamine was significantly reduced in patients premedicated with diazepam. Psychotomimetic side effects were not prominent in any of the groups. Patients premedicated with diazepam required a lower rate of ketamine infusion as compared to controls during the initial 30 min of anaesthesia. The patients in the other groups did not differ from the control group in this respect. There were large differences in metabolic pattern between the groups. As compared to the controls, the patients on long-term diazepam or barbiturates had high concentrations of hydroxylated metabolites, with levels higher than that of norketamine. The patients pretreated with diazepam had very low plasma levels of hydroxylated metabolites. Clorazepate premedication did not significantly affect the metabolism of ketamine. The biological half-life of ketamine was significantly increased in the diazepam-treated group, and it was shortened in those on long term treatment with barbiturates or diazepam.
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  • 65
    ISSN: 1432-1041
    Keywords: theophylline ; sustained release tablet ; absolute bioavailability ; pharmacokinetics ; individual dosage regimen
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The systemic disposition of theophylline after taking a new, sustained release tablet (Theolair Retard® 250 mg, Theolair S. R.®, Riker Laboratories) has been studied in 8 hospitalized patients. Absolute bioavailability was determined from the ratios of the areas under the serum concentration-time curves after intake of the tablet and after intravenous infusion of aminophylline in the same patient. The absolute bioavailability of Theolair Retard® 250 mg was 110.9±20.8% (mean ± SD). Maximal serum concentrations were reached after 7.3±3.5 h, the large intersubject variation being due to differences in gastric emptying time. The tablets appear to release theophylline slowly in acid conditions, but more rapidly in an alkaline medium. Invasion was found to be either monophasic with a rate constant of about 0.8 h−1 (intestine), or biphasic with rate constants of 0.2 h−1 (stomach) and 0.8 h−1 (intestine). The peak levels accounted for 7.9±2.2 mg · 1−1. The profiles of the serum concentration-time curves were such that the concentrations remained above 80% of cmax for 6.5±3.3 h. The relevant pharmacokinetic parameters (half-life of elimination, total body clearance and volume of distribution) were determined and were used to calculate the individual dosage regimens required to obtain therapeutic serum concentrations. The optimal dosing interval to obtain an average steady state serum concentration of 12.5 mg · l−1 was 9.8±3.1 h.
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  • 66
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    European journal of clinical pharmacology 21 (1981), S. 61-64 
    ISSN: 1432-1041
    Keywords: acenocoumarol ; anticoagulant therapy ; breast feeding ; breast milk ; neonatal thrombotest ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In 20 women receiving Sintrom® post partum, the acenocoumarol concentration in serum and breast milk at different times was measured. Even at the time of maximal serum concentration, or for the following 6 h, no acenocoumarol could be detected in the breast milk. In accordance with this finding, no effect of breast feeding on Thrombotest values of the infants could be demonstrated. These data suggest that mothers taking acenocoumarol for a short period may safely breast feed their infants.
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  • 67
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    European journal of clinical pharmacology 21 (1981), S. 45-52 
    ISSN: 1432-1041
    Keywords: caffeine ; pharmacokinetics ; plasma ; saliva ; urinary elimination
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Plasma and salivary caffeine concentrations were measured by gas-liquid chromatography in 6 healthy caffeine-free volunteers following oral administration of 50, 300, 500 and 750 mg caffeine. Caffeine was also given to a single subject intravenously in doses of 300, 500 and 750 mg. Caffeine was rapidly absorbed and was completely available at all doses. The apparent first-order elimination rate constant decreased linearly with dose and was 0.163±0.081 h−1 for 50 mg and 0.098±0.027 h−1 for 750 mg. The total body clearance was unaffected by dose and was 0.98±0.38 ml/min/kg. There was a trend towards increasing apparent volume of distribution with increasing dose. A linear relationship existed between the area under the plasma concentration, time curve and dose and dose-normalised plasma concentration, time plots were superimposable. These findings suggest that caffeine obeys linear pharmacokinetics over the dose range investigated. Despite significant inter-individual differences in pharmacokinetic parameters there was good reproducibility within 5 subjects given 300 mg caffeine orally on 3 occasions. Salivary caffeine levels probably reflect the unbound plasma caffeine concentration and can be used to estimate the pharmacokinetic parameters of the drug. Overall the saliva/plasma concentration ratio was 0.74±0.08 but within subjects some time-dependence of the ratio was found with higher ratios initially (even after intravenous administration) and lower ratios at longer time intervals after the dose. Urinary elimination of caffeine was low and independent of dose: 1.83% of the dose was eliminated unchanged.
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  • 68
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    European journal of clinical pharmacology 24 (1983), S. 485-494 
    ISSN: 1432-1041
    Keywords: amiodarone ; pharmacokinetics ; therapeutic serum level ; thyroid function ; antiarrhythmic therapy ; adverse effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In 17 patients on long term therapy with amiodarone, serum drug levels measured by HPLC were related to pharmacological effects. At steady state, serum levels were directly proportional to the dose, 5 mg/kg per day leading to an average serum level of approximately 2.5 µmol/l. The non-amiodarone level of iodine averaged 4-times higher than the level of amiodarone iodine. The elimination half-life of amiodarone ranged from 21 to 78 days, and of non-amiodarone iodine from 24 to 160 days. Control of arrhythmias was satisfactory in all 12 evaluable patients, when the serum amiodarone level exceeded 1.5 µmol/l. Deterioration of vision and polyserositis occurred only at amiodarone levels above 4 µmol/l. Tentatively, a therapeutic range of 1.5 to 4 µmol/l is proposed. In contrast, thyroid dysfunction was observed at any amiodarone level. In view of the narrow therapeutic window, therapy with amiodarone may be optimized by monitoring its serum level and in addition, thyroid function should be regularly checked.
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    European journal of clinical pharmacology 24 (1983), S. 521-524 
    ISSN: 1432-1041
    Keywords: sotalol ; beta-adrenoceptor antagonist ; pregnancy ; pharmacokinetics
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Sotalol, a beta-adrenoceptor blocking drug, was administered to 6 healthy pregnant volunteers between 32–36 weeks gestation and when at least 6 weeks post-partum. On both occasions, each volunteer was given sotalol 100 mg intravenously and 400 mg orally in randomised order with at least a 1 week washout period between. Plasma samples were analysed for sotalol using a fluorometric method and the pharmacokinetic profiles investigated. The systemic clearance of sotalol was significantly greater in the antenatal period (2.4±0.3 ml/min/kg) than in the post-natal phase (1.5±0.1 ml/min/kg). The apparent volume of distribution was similar in the two periods: the elimination half-life was 6.6±0.6h ante-natally and 9.3±0.7h post-natally after intravenous drug but the trend for faster elimination was not significant. The elimination half-life after oral administration (about 10h) and bioavailability (about 90%) were not altered significantly by pregnancy. It is suggested that the more rapid clearance of sotalol in pregnancy may be due to increases in renal plasma flow and glomerular filtration rate.
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  • 70
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    European journal of clinical pharmacology 24 (1983), S. 549-556 
    ISSN: 1432-1041
    Keywords: dibromosulfophthalein ; pharmacokinetics ; plasma levels ; urinary excretion ; biliary excretion ; biliary fistula ; enterohepatic circulation ; hepatic transport test
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of dibromosulfophthalein (DBSP), the 3,6-dibromo analogue of BSP, was studied in 7 patients with a biliary fistula, 52 h after cholecystectomy, and in 6 gynaecological patients with an indwelling urethral catheter, following extirpation of the uterus i.e. with an intact enterohepatic circulation. Plasma protein binding determined by ultrafiltration was 98–99% up to a concentration of 700 µg/ml. After an intravenous bolus injection of DBSP 5 mg/kg, a biexponential plasma decay was found in both groups, with a rapid initial t1/2 of 2–6 min and a slow secondary phase of 33–109 min (mean 66 min) in the cholecystectomy patients, and 10–30 min (mean 19 min) in the gynaecological patients. The biliary excretion rate varied considerably between the patients and was highly correlated with bile flow. Biliary output amounted to a maximum of 86% of the dose in 24 h. The excretion rate curves showed ascending and descending phases, the mean terminal t1/2 being 65 min. Urinary excretion was 3–11% of the dose in 8 h in the gynaecological patients (mean 6%) and 6–31% in the cholecystectomy group (mean 16%). Renal clearance of unbound DBSP was about ten-times greater than the glomerular filtration rate, which indicates tubular secretion. A two compartment model with elimination from the peripheral and central compartments was selected because of these data. Analysis of the plasma-disappearance curves indicated an initial plasma clearance of 500–600 ml/min, which suggests that hepatic uptake will be very dependent on flow. Steady state (biliary) clearance was about 400 ml/min in the gynaecological group and approximately half that in the cholecystectomy patients; V1 tended to be higher and V2 to be lower in the latter group. It is concluded that biliary excretion rate of DBSP in patients with a biliary fistula is probably depressed by the postoperative bile drainage and the lack of enterohepatic cycling of bile salts.
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    European journal of clinical pharmacology 24 (1983), S. 661-665 
    ISSN: 1432-1041
    Keywords: hydrochlorothiazide ; pharmacokinetics ; renal failure ; dosage adjustment ; excretory mechanism
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of hydrochlorothiazide (HCT) was investigated in 23 subjects with normal renal function or widely varying degrees of renal failure. The half-life of elimination increased from 6.4 h in subjects with normal renal function to 11.5 h in patients with mild renal impairment (endogenous creatinine clearance between 30 and 90 ml/min), and to 20.7 h in patients with an endogenous creatinine clearance below 30 ml/min. The cumulative urinary excretion and the renal HCT clearance were correspondingly reduced in patients with impaired kidney function. In normal subjects HCT was mainly excreted by tubular secretion, but as renal HCT clearance in patients with renal impairment did not differ significantly from endogenous creatinine clearance, it was concluded that the secretory mechanism is most markedly impaired. In patients with an endogenous creatinine clearance of 30 to 90 ml/min, the dosage of HCT should be reduced to 1/2 and in patients with a endogenous creatinine clearance below 30 ml/min to 1/4 of the normal daily dose to avoid dose dependant side-effects.
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  • 72
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    European journal of clinical pharmacology 24 (1983), S. 813-818 
    ISSN: 1432-1041
    Keywords: dihydroergotamine ; dextran 70 ; pharmacokinetics ; radioimmunoassay ; drug interaction
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of subcutaneous dihydroergotamine (DHE) with or without dextran 70 infusion was evaluated in a single- and multiple-dose study in 30 patients. Radioimmunoassay was used to measure plasma DHE and the anthrone method to determine the dextran concentration. In the single-dose study no significant interaction between DHE and dextran was noted with respect to their plasma levels. The absorption of s.c. DHE was rapid and the disappearance curve followed a biphasic pattern, t0.5 α being 1.4 and 2.0 h, t0.5 β 22 and 21 h for DHE and DHE/dextran 70, respectively. In the multi-dose study the trough level of DHE initially had a tendency to rise, in accordance with simulated plasma concentration curves. DHE trough levels were about 0.5 ng/ml and were well above the assumed minimum effective value to induce venoconstriction (0.06 ng/ml). Dextran concentrations were significantly higher when DHE was co-administered, possibly, due to changes in plasma volume. It is concluded that DHE 0.5 mg s.c. twice daily will give an adequate plasma concentration and that there was no important interaction between it and infused dextran 70.
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    European journal of clinical pharmacology 25 (1983), S. 77-80 
    ISSN: 1432-1041
    Keywords: meptazinol ; pharmacokinetics ; multiple dosing ; plasma protein binding ; analgesic
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of meptazinol (Meptid®) have been studied in nine male volunteers after single and multiple oral administration of 200 mg tablets and also after a single 25 mg intravenous dose. Plasma concentrations of meptazinol were determined by HPLC using fluorescence detection. Drug absorption after oral dosage was rapid, peak plasma concentrations being reached between 0.25 and 2 h after drug administration. Subsequent elimination proceeded in an apparently mono-exponential fashion with a half-life of 2 h, although after intravenous dosage there was evidence of an initial rapid distributive phase. The mean total plasma clearance was 2.21/min and the mean apparent volume of distribution (Vdβ) was 4.99 l/min. The bioavailability ranged from 1.9 to 18.5% (mean=8.7%) and was related to the rate of absorption. Multiple dosing, 6-hourly for 3 days, did not produce any accumulation above that predicted from a single dose. Plasma protein binding of the drug was 27.1% and did not vary over the therapeutic concentration range of 25 to 250 ng/ml.
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  • 74
    ISSN: 1432-1041
    Keywords: carteolol ; pharmacokinetics ; beta-adrenoreceptor blocking drug ; absolute bioavailability ; plasma levels ; urinary excretion ; renal handling
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics and absolute bioavailability of a new nonselective β-adrenoreceptor blocking agent, carteolol, were investigated after administration of single intravenous and oral doses to eight normal volunteers. Plasma and urine drug concentrations were measured by an HPLC method. The pharmacokinetic parameters after intravenous dosing were obtained by a two-compartment analysis: elimination or β-phase t1/2 4.7±0.3 h; Vc, 0.74±0.101/kg; Vd, 4.05±0.48 l/kg; Cl, 10.13±0.94 ml/min/kg; ClR, 6.56±0.58 ml/min/kg; and ClNR, 3.57±0.40 ml/min/kg. The absolute bioavailability obtained from plasma data was 83.7±8.0%, which was consistent with that derived from analysis of urine of 82.7±4.2%. The amounts excreted unchanged in urine up to 48 h after the intravenous and oral doses were 65.0±1.5% and 53.8±3.2% of the administered doses, respectively. The t1/2 for removal of the drug derived from plasma and urine findings after intravenous and oral dosing were similar, which indicates that the main route of elimination of carteolol is via the kidneys. As the ClR of carteolol exceeded the Cl of creatinine there may be renal tubular secretion of the drug.
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  • 75
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    European journal of clinical pharmacology 25 (1983), S. 237-241 
    ISSN: 1432-1041
    Keywords: triamterene ; bioavailability ; pharmacokinetics ; metabolism ; hydroxy triamterene sulphate ; urinary excretion ; i.v. administration ; first-pass-effect
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary With a new formulation, which made intravenous infusion of triamterene (TA) possible, plasma levels and urinary excretion rates of TA and its main metabolite (OH-TA-ester) were measured in a randomized, cross-over trial in 6 healthy volunteers given triamterene 10 mg i.v. and 50 mg p.o. TA and OH-TA-ester were determined by densitometric measurement of native fluorescence after thin layer chromatography. Distribution volumes of the central compartment of TA and OH-TA-ester were 1.49 l/kg and 0.11 l/kg, respectively. Terminal half-lives were 255 min for TA and 188 min for OH-TA-ester after i.v. administration. For TA total plasma clearance was 4.5 l/min and renal plasma clearance 0.22 l/kg. The formation of OH-TA-ester was very rapid and the concentration of the metabolite exceeded that of TA at all times. After i.v. administration the urinary recovery of TA and OH-TA-ester was 4.4% and 50.9%, respectively. The bioavailability of TA was 52%, corresponding to absorption of 83%. TA is partly eliminated by a first-pass-effect. The main metabolite of TA is OH-TA-ester, which is pharmacologically active.
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  • 76
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    European journal of clinical pharmacology 25 (1983), S. 369-373 
    ISSN: 1432-1041
    Keywords: pengitoxin ; pharmacokinetics ; 16-acetylgitoxin ; absorption ; urinary excretion ; healthy subjects ; cardiac glycoside
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of pengitoxin has been studied in 28 healthy subjects after intravenous and oral administration. The mean plasma concentration 24 h after 0.5 mg i.v. was 5.2 ng · ml−1. Following an open two-compartment model a mean elimination half-life of 60.5 h (24.9 to 103.5 h) and a mean volume of distribution (Vdarea) of 66.91 (31.8 to 109.61) were calculated. Absorption calculated by comparison of the AUC0-∞-values amounted to 99%. Within 4 days, 16.7% (11.7 to 21.1%) or 27.8% (18.4 to 33.7%) (0.5 mg i.v. or 1.2 mg p.o.) was excreted in urine. After pengitoxin 0.5 mg i.v. total body clearance and renal clearance were 13.3 ml · min−1 (7.0 to 18.6 ml · min−1) and 3.0 ml · min−1 (1.9 to 3.9 ml · min−1) respectively. The elimination half-life of pengitoxin is longer than that of digoxin and distinctly shorter than that of digitoxin, whilst its distribution volume and clearance are closer to those of digitoxin than of digoxin.
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  • 77
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    European journal of clinical pharmacology 25 (1983), S. 399-405 
    ISSN: 1432-1041
    Keywords: ceftriaxone ; pharmacokinetics ; concentration-dependent binding ; volume of distribution
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary We have theoretically examined the influence of plasma protein binding (specifically the fraction unbound, fp) on the pharmacokinetic parameters following rapid injection of a drug undergoing concentration-dependent binding. Particular emphasis was placed on the apparent volume of distribution terms based on both total and unbound drug concentrations. Computer simulations were performed to establish the validity and utility of such relationships. The following observations were made: a) distributional parameters based on total drug (both Vβ and the model-independent VSS) were inaccurate/invalid; b) V β based on unbound drug was misleading; c) the model-independent VSS for unbound drug accurately predicted the steady state situation. Furthermore, two new terms ( $$\bar f_P $$ and $$\bar V_{SS}^T $$ ) were introduced which provide additional insight concerning the disposition of this type of drug. The $$\bar f_P $$ is the area-weighted average fraction unbound in the plasma and $$\bar V_{SS}^T $$ is the corrected steady state distribution term for total drug levels. The present study indicates that useful distributional and clearance terms can be calculated for this type of drug, provided that the time course of unbound drug as well as total drug can be followed. Moreover, guidelines for their extrapolation to steady state conditions and their correct interpretations are discussed.
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  • 78
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    European journal of clinical pharmacology 25 (1983), S. 455-457 
    ISSN: 1432-1041
    Keywords: digoxin ; concentration plateau ; pharmacokinetics ; systolic time intervals ; optimal infusion scheme ; dose-response data
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Using a volume-controlled infusion pump, a mean serum plateau level of digoxin of 4–5 ng/ml was rapidly achieved and maintained in 6 healthy volunteers. The infusion scheme was calculated on the basis of data published on the pharmacokinetics and pharmacodynamics of digoxin following bolus intravenous injection. The magnitude of the response (change in electromechanical systole) at the end of the plateau phase was comparable to that observed with the concentration in the therapeutic range at steady state.
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  • 79
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    European journal of clinical pharmacology 25 (1983), S. 449-453 
    ISSN: 1432-1041
    Keywords: canrenone ; pharmacokinetics ; plasma level ; bioavailability ; urinary excretion ; spironolactone
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Five healthy male volunteers received canrenoate-K 200 mg (Sincomen® pro injectione) by intravenous injection and one week later spironolactone 200 mg (Sincomen®-100) orally. Plasma levels and urinary excretion of unchanged canrenone were determined up to 24 h by a specific HPLC method. Following intravenous administration, the maximum plasma level of 2066±876 ng/ml was found after 29±15 min and thereafter the concentration declined with a half-life of 3.7±1.2 h. Total clearance was 4.2±1.7 ml/min·kg. After oral ingestion, the maximum concentration of 177±33 ng/ml was observed at 4.4±0.9 h. The absolute bioavailability of canrenone was 25±9%. Within 24 h, respectively 0.4 and 0.6 mg, canrenone were excreted by the kidney after intravenous and oral administration. The half-life of elimination was 4.9±1.8 h (i.v.) and 3.9±1.2 h (p.o.).
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  • 80
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    European journal of clinical pharmacology 25 (1983), S. 497-501 
    ISSN: 1432-1041
    Keywords: methadone ; pharmacokinetics ; steady state ; addiction rehabilitation ; therapeutic failure
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Deuterated methadone (M-d3) and GC-MS analysis were used to study the steady state pharmacokinetics of methadone (M) in eight patients reported as therapeutic failures in a methadone maintenance treatment programme. The patients were compared to an unselected group of 12 patients stabilized on M for 25 days. During one dosage interval a pulse dose of M-d3 was administered intravenously instead of the oral M-dose (M-d0). The pharmacokinetic parameters, half-life in the β-phase (t1/2β), volume of distribution during the postdistributive phase (Vdβ) and during steady state (Vdss) were determined as well as the body (ClS) and renal (ClR) clearances of M. Pronounced differences in Vdβ and Vdss were found between the two groups. The therapeutic failures had a smaller Vdβ and Vdss 3.09±0.96 l/kg and 2.74±0.96 l/kg vs 4.56±1.00 l/kg and 4.20±0.78 l/kg in the control group. The differences were due to changes between the groups in the volume of the central compartment. Differences between the groups were also found in t1/2β — 24.5±2.6 h in the therapeutic failures and 34.0±7.0 h (p〈0.001) in the comparison group. However, the change in t1/2β was probably a consequence of the change in Vdβ, as the body clearance of M was similar in the two groups — 104±36 ml/min vs 111±36 ml/min. The smaller volume of distribution could lead to unacceptably high fluctuation of M in the central compartment, and withdrawal symptoms during the latter part of the dosage interval. The appropriate treatment of this subgroup of patients on methadone treatment is not to increase the dose but to shorten the dosage interval. Alternatively, a longer-acting opiate, such as 1-α-acetylmethadol (LAAM), may be used.
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  • 81
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    European journal of clinical pharmacology 25 (1983), S. 529-534 
    ISSN: 1432-1041
    Keywords: penbutolol ; pharmacokinetics ; blood pressure effect ; heart rate effect ; dose response relationship ; tolerance
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The present study was done to establish the dose-response relationships for effects on heart rate and systolic and diastolic blood pressure, tolerance and plasma disappearance kinetics after large intravenous and oral doses of penbutolol. Twelve healthy volunteers were randomly allocated to receive penbutolol (n=8) or placebo (n=4) in this single blind, placebo-controlled investigation. The degree of beta-blockade was measured by standarized exercise tests at work loads selected to produce a heart rate of 150/min without treatment. Penbutolol was given as single i.v. doses of 3, 6 and 12 mg and as 40, 80 and 120 mg once daily for one week, measurements being made 2 and 24 h after the last dose. Penbutolol i.v. did not influence the resting heart rate but it did reduce resting systolic blood pressure in a non-dose dependent manner. Exercise heart rate and systolic pressure were lowered by all the intravenous doses. All oral doses of penbutolol lowered exercise heart rate and systolic blood pressure to the same extent. The reductions in exercise tachycardia was still present after 24 h. After i.v. administration t1/2 was approximately 1.2 h and the volume of distribution was 32–42 l. All doses were well tolerated.
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  • 82
    ISSN: 1432-1041
    Keywords: delta-9-tetrahydrocannabinol ; mood ratings ; pharmacodynamics ; pharmacokinetics
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary This study explored the relationships in man between various pharmacological effect of Δ9-tetrahydrocannabinol (THC), plasma THC concentration, and pharmacokinetic parameters of THC. Three male and three female experienced marihuana users smoked two standard marihuana cigarettes. The relationships between heart rate, subjective “high” rating, Linear Mood Scale factors, and plasma THC concentration were assessed. Significant correlations were observed between various Linear Mood Scale factors and pharmacokinetic parameters reflecting the magnitude of drug intake and the degree of temporal dissociation between the time courses of plasma THC concentration and pharmacological effects (tachycardiac effect, “high”). In particular, the disturbed/weird and sensitive/aware mood factors correlated positively with pharmacokinetic measures of drug intake and time lag to effect. A more reliable index of intoxication with THC may be provided by the global subjective “high” rating, rather than other ratings more specific for particular moods.
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  • 83
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    European journal of clinical pharmacology 23 (1982), S. 1-5 
    ISSN: 1432-1041
    Keywords: clonidine ; noradrenaline ; pharmacokinetics ; arterial blood pressure ; plasma concentration
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of clonidine and its relation to blood pressure response and side effects were studied after single oral doses of 75 µg, 150 µg and 250 µg in normotensive subjects. Following oral administration, the drug was absorbed rapidly after an initial lag time of 19–22 min and peak levels were reached between 2.4 and 2.9 h. Sampling over 48 h was necessary for accurate estimation of pharmacokinetic parameters. Post-peak plasma concentration declined in a monoexponential manner and the half-life of the elimination phase ranged from 9.0 to 15.1 h. Maximum plasma concentration (Cmax) and area under curve (AUC) increased proportionally with increasing doses. Clonidine produced significant reductions in the pulse rate and a dose dependent decrease in blood pressure. Clonidine (150 µg) also produced significant reductions in plasma catecholamine levels.
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  • 84
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    European journal of clinical pharmacology 23 (1982), S. 43-47 
    ISSN: 1432-1041
    Keywords: timolol ; pharmacokinetics ; pharmacodynamics ; healthy subjects ; cardiac infarction patients ; i.v. therapy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Disappearance pharmacokinetics, pharmacodynamics and general tolerance of i.v. timolol were compared in 12 healthy volunteers and 10 patients with a definite or proven acute myocardial infarction. The drug was administered to the patients immediately on arrival at the hospital after a median delay time of 4 h. Tolerance to the injections was good in both volunteers and patients. The study revealed disappearance pharmacokinetics that were similar in volunteers and patients.
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  • 85
    ISSN: 1432-1041
    Keywords: cyclobarbital ; aminopyrine ; liver disease ; 14CO2 breath test ; barbiturate ; pharmacokinetics ; hepatic drug metabolism ; cirrhosis ; alcoholic liver disease ; viral hepatitis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The exhalation of 14CO2 derived from an i.v. tracer dose of [dimethylamine-14C]aminopyrine has been investigated in normal controls and patients. They subsequently ingested 200 mg cyclobarbital calcium in the evening and the decline in the plasma drug level over the following 2 days was measured by thin-layer chromatography. The peak specific activity of exhaled 14CO2 occurred 0.5–2 h after 14C-aminopyrine injection in the absence of liver disease and in non-cirrhotic liver disorders. It was delayed in certain patients with cirrhosis. Compared to 8 medically healthy subjects, 10 patients with acute viral hepatitis, 8 with cirrhosis and 10 with fatty liver exhibited a significantly increased half-life of 14CO2 exhalation. Normal mean values were found in 12 patients with non-cirrhotic alcoholic liver disease and in 14 patients with non-hepatic diseases. The cyclobarbital (CB) half-life was prolonged and the clearance reduced in patients with viral hepatitis, cirrhosis, or alcoholic liver damage as compared to data from 17 control subjects. Due to a larger apparent volume of distribution, patients with fatty liver disease had an increased CB half-life, although its clearance was normal. A close negative correlation was detected between the clearance and the logarithm of the CB level measured 36 h after drug ingestion. The oral CB test evaluated from a single blood sample taken about 36 h after drug administration appears to be a useful indicator of human drug metabolising capacity. Discrimination between patients with and without disordered liver function was similar in the two drug elimination tests.
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  • 86
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    European journal of clinical pharmacology 26 (1984), S. 121-124 
    ISSN: 1432-1041
    Keywords: methotrexate ; psoriasis ; pharmacokinetics ; plasma levels ; urinary excretion ; renal clearance ; tubular absorption
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The plasma concentration and urinary excretion of methotrexate were followed in twelve psoriatic patients after intravenous and oral doses of methotrexate ranging from 7.5 to 30 mg. In six of the patients, a nonlinear relation was found between the fractional amount of methotrexate excreted in the urine and the corresponding area under the plasma concentration-time curve. The methotrexate clearance was found to be increased during the initial high plasma concentration, probably due to saturation of the tubular reabsorption of methotrexate. Considerable interindividual variation was found in the apparent saturation point of the active reabsorption, but up to 500–800 ng/ml first order kinetics still applied. At plasma concentrations below saturation, the renal clearance of methotrexate ranged from 52–102 ml/min (mean±SD, 83±19.4 ml/min).
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  • 87
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    European journal of clinical pharmacology 26 (1984), S. 87-93 
    ISSN: 1432-1041
    Keywords: enprofylline ; pharmacokinetics ; renal elimination ; renal insufficiency ; healthy subjects ; creatinine clearance ; side effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Enprofylline, a new bronchodilating drug, was given i.v. at 1.0 mg/kg to 7 healthy subjects and to 14 patients with differing degrees of chronic renal insufficiency. Plasma and urine concentrations of unchanged drug were followed by HPLC. In the patients the plasma half-life was prolonged and the total and renal clearances were reduced in direct proportion to the degree of renal insufficiency as determined by creatinine clearance. The unbound fraction of enprofylline in plasma increased from 55% in the healthy subjects to 66% in the group of patients with the highest degree of renal impairment. The volume of distribution terms, Vβ and Vss, both tended to decrease with decreasing creatinine clearance. When the volume term calculations were based on the unbound drug level in plasma, this tendency was enhanced. Side-effects were noted in 4 subjects, and to some extent were related to the plasma level of the drug.
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  • 88
    ISSN: 1432-1041
    Keywords: sulphapyridine ; sulphasalazine ; pharmacokinetics ; rectal administration ; oral administration ; plasma levels ; ulcerative colitis
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Rectal administration of sulphasalazine to patients with ulcerative colitis has recently been shown to have similar therapeutic activity but fewer side effects than oral treatment. The present study is a comparison of the pharmacokinetics of sulphasalazine (SASP) and its metabolite sulphapyridine (SP) after rectal and oral administration of SASP to 6 patients with ulcerative colitis. The areas under the concentration-time curves (AUC) and the maximum concentrations (Cmax) of SASP and SP were significantly lower after rectal than oral administration of SASP (p〈0.05). These findings support the view that the lower frequency of side effects after rectal administration of SASP may result from the lower plasma levels of SASP and SP.
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  • 89
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    European journal of clinical pharmacology 26 (1984), S. 309-313 
    ISSN: 1432-1041
    Keywords: clonidine ; hypertension ; therapeutic window ; steady state concentration ; pharmacokinetics ; cardiovascular effects
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Clonidine was given orally as monotherapy in increasing daily doses from 3.1 to 25.7 µg/kg to patients with essential hypertension (n=6). When a steady state concentration in plasma was reached at each dose level, the blood pressure (BP) and heart rate were measured during a dosage interval. Effect time — plasma concentration data were submitted to nonlinear regression analysis, which showed that the observed BP effects could be dissociated into depressor and pressor components. A window for the antihypertensive effect was established. At a plasma clonidine concentration of 0.65±0.07 ng/ml 50% of the maximal depressor effect was found, and it was only separated by a factor of 2 from the half maximal pure pressor concentration in plasma. No relationship between the change in heart rate and the plasma clonidine was observed. The findings strengthen the importance of close monitoring of clonidine therapy.
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  • 90
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    European journal of clinical pharmacology 26 (1984), S. 381-388 
    ISSN: 1432-1041
    Keywords: midazolam ; hypnotic drug ; benzodiazepine ; pharmacokinetics ; aged patients
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of midazolam, an imidazo-benzodiazepine derivative, have been studied in 13 subjects over the age of 60 years who received the drug intravenously (0.07 mg kg−1) as an induction agent for endoscopy. Two to three days later, 6 of these subjects received 5 mg of midazolam intramuscularly, and another 6 of the subjects received 10 mg of the drug orally. The plasma concentration-time curves were again studied pharmacokinetically. After intravenous dosing, the mean (± SD) elimination half-life (2.14±1.24 h) showed a statistically significant trend to increase with age in the subjects older than 60 years. While the mean (± SD) clearance value (0.30±0.19 l kg−1h−1) tended to fall with age in the elderly subjects, this trend was not statistically significant. Apparent volume of distribution did not appear to be related to advancing age beyond 60 years, and this parameter (mean ± SD) did not differ to a statistically significant extent between the aged subjects (0.77±0.47 l kg−1) and the young subjects studied previously (1.09±0.58 l kg−1). Atropine premedication did not appear to alter the dispositional parameters of the intravenously administered drug. Intramuscularly administered midazolam was absorbed rapidly. Bioavailability appeared incomplete (F=0.59±0.15, mean ± SD), possibly due to saturable elimination of the drug at the higher plasma levels which were obtained after intravenous midazolam. Oral bioavailability, relative to intravenous, was 0.34±0.17, (mean ± SD), with an appreciable but variable lag time (0.74±0.40 h, mean ± SD). Orally, in the dose used, the drug was an inefficient hypnotic with four of the six subjects failing to attain the plasma drug level of 44–50 µg l−1, which appeared to be the approximate threshold for sleep. It is impossible to know whether this failure represents an age related effect on drug absorption, or is a consequence of the upper alimentary tract abnormalities for which the endoscopies were done.
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  • 91
    ISSN: 1432-1041
    Keywords: cefoxitin ; beta-lactam antibiotics ; pharmacokinetics ; serum concentration ; pleural fluid concentration
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of cefoxitin was studied in 6 healthy volunteers and in 5 patients with a pleural effusion after administration of a single dose of 30 mg/kg i.v. infusion. The serum and pleural fluid concentrations of cefoxitin were determined microbiologically. The elimination half-life of the antibiotic from pleural fluid in all cases was 2–3fold longer than from serum, which shows a difference between the kinetic elimination processes of the antibiotic from the two fluids. The slow elimination of cefoxitin from pleural fluid facilitates its accumulation in this compartment during a multiple dosage regimen.
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  • 92
    ISSN: 1432-1041
    Keywords: cefoperazone ; peritoneal dialysis ; pharmacokinetics ; terminal renal failure ; peritonitis
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of cefoperazone after i.p. and/or i.v. administration were studied in 12 CAPD patients. After i.v. injection, the plasma half-life was 2.65±0.4 h, the total clearance amounting to 70.1±19.2 ml/min. Peritoneal clearance was calculated to be 6.9±1 ml/min. After peritoneal instillation, the bioavailability was 63.9±5%. After repeated i.p. administration, no accumulation of the drug in the body was observed. Thus, cefoperazone can be safely administered for the treatment of peritonitis in CAPD patients.
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  • 93
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    European journal of clinical pharmacology 26 (1984), S. 651-653 
    ISSN: 1432-1041
    Keywords: prednisolone ; prednisone treatment ; pharmacokinetics ; individual variation ; microsomal enzyme induction
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Eleven patients on long-term prednisone treatment were studied on two occasions separated by 45 to 325 days. In 10 patients the total body clearance of prednisolone only changed about 10%. In one case a 78.5% decrease was observed after stopping treatment with rifampicin and isoniazide. No association was found between the prednisone dose rate (mg/kg per month), patient age or mean endogenous plasma hydrocortisone level and prednisolone clearance/kg. The results indicate considerable intra-individual consistency of prednisolone kinetics if other conditions are not changed.
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  • 94
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    European journal of clinical pharmacology 26 (1984), S. 749-752 
    ISSN: 1432-1041
    Keywords: dextropropoxyphene ; pharmacokinetics ; half-life ; 3-compartment model ; steady state prediction ; plasma levels
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Data from a previously published single dose study of d-propoxyphene 65 mg given i.v. to 8 healthy subjects have been subjected to non linear regression analysis by a curve-fitting program to test the applicability of a 2- and a 3-compartment open model. Analysis of residuals (difference between observed and computed concentrations) revealed similar systematic deviations in all 8 subjects when the 2-compartment model was used (5–10 h negative residuals, after 13 h positive residuals). In contrast, curve-fit by a 3-compartment model (with two parallel peripheral compartments) was good with no systematic deviations. The data show that a terminal monoexponential decline in d-propoxyphene concentrations cannot be expected until 15–30 h after single dose administration, and that the determination of the corresponding half-life is rather inaccurate. Accordingly, precise steady state level predictions may be difficult to obtain from conventional single dose studies with d-propoxyphene.
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  • 95
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    European journal of clinical pharmacology 27 (1984), S. 105-110 
    ISSN: 1432-1041
    Keywords: phenytoin ; epileptic women ; pharmacokinetics ; bioavailability ; pregnancy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Five epileptic women needing to commence phenytoin therapy during pregnancy received a single intravenous and a single oral dose of phenytoin several days apart before starting regular intake of the drug. Plasma phenytoin concentration — time data were analysed by three different pharmacokinetic techniques. However assessed, the mean oral bioavailability of the drug proved to be about 90% of the intravenous bioavailability. This finding makes it unlikely that impaired bioavailability accounts for the increase in oral phenytoin dosage necessary in pregnancy to maintain plasma phenytoin concentrations at pre-pregnancy values. Phenytoin clearance in the pregnant subjects was approximately double the published values for phenytoin clearance in nonpregnant persons. This suggests that increased (metabolic) clearance accounts for the increased phenytoin dosage requirement of pregnancy.
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  • 96
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    European journal of clinical pharmacology 27 (1984), S. 159-163 
    ISSN: 1432-1041
    Keywords: endralazine ; renal impairment ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The influence of renal impairment on the pharmacokinetics of endralazine was studied in 12 patients; 4 patients on regular haemodialysis therapy (creatinine clearance less than 5 ml/min) and 8 patients with varying degrees of renal impairment (creatinine clearance 11–52 ml/min). Following an oral dose of 10 mg endralazine the mean terminal elimination half-life (βt1/2) in the dialysis sub-group was prolonged at 7.1 h (range 3.3 to 14 h), compared to 3.6 h in the other renal patients (and compared to 2.3 h in hypertensive patients with normal renal function). After one week's therapy with 10 mg B.D. endralazine in the 8 patients with moderate renal impairment there was a significant increase in βt1/2 to 8.6 h but there was no significant change in the area under the drug concentration-time curve and no evidence of drug accumulation. In this study those patients with the poorest renal function had the longest βt1/2 after acute dosing. There was a significant correlation between creatinine clearance and acute βt1/2 but there was considerable variability in individual patients and, even with severe degrees of renal impairment, major dose adjustments do not appear necessary.
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  • 97
    Electronic Resource
    Electronic Resource
    Springer
    European journal of clinical pharmacology 25 (1983), S. 117-121 
    ISSN: 1432-1041
    Keywords: serum digoxin ; pregnancy ; digoxin-renal-clearance ; creatinine-clearance ; digoxin-elimination ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Digoxin-renal-clearance, creatinine-clearance, 24-h urine elimination of digoxin and serum digoxin were studied in 15 patients in the third trimester of pregnancy and 6 to 12 weeks post-partum. There was significant fall post-partum in the first three. There was also a significant fall post-partum in serum digoxin levels. This finding was unexpected, but may be due to heightened absorption exceeding increased elimination because of the physiological status in pregnancy.
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  • 98
    ISSN: 1432-1041
    Keywords: sotalol ; hydrochlorothiazide ; pharmacokinetics ; moderate renal failure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Decreased elimination of a combined formulation of Sotalol (160 mg) and hydrochlorothiazide (25 mg) was found in patients with moderate renal insufficiency. Very slight accumulation of sotalol and hydrochlorothiazide was observed, so it appears unnecessary to reduce the dosage in patients with a creatinine clearance of 30 ml/min or more.
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  • 99
    Electronic Resource
    Electronic Resource
    Springer
    European journal of clinical pharmacology 27 (1984), S. 583-587 
    ISSN: 1432-1041
    Keywords: propranolol ; pregnancy ; beta-adrenoceptor antagonist ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Propranolol, a beta-adrenoceptor blocking drug, was administered to 6 healthy pregnant volunteers between 32 and 36 weeks gestation and when at least 6 weeks postparum. On both occasions, subjects were given propranolol 120 mg orally or 10 mg intravenously in randomised order with a minimum washout period of 1 week. Propranolol was assayed in plasma by gas-liquid chromatography with electron-capture detection and the pharmacokinetic parameters were investigated. There were no significant alterations in elimination half-life, clearance or apparent volume of distribution per kilogram antenatally compared with postnatally: bioavailability was also unchanged. It is concluded that the disposition of propranolol is not altered during pregnancy.
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  • 100
    ISSN: 1432-1041
    Keywords: Bezitramide ; oral absorption profile ; pharmacokinetics ; male volunteers ; experimental pain ; biliary excretion in rats
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The oral absorption of bezitramide 5 mg was studied in 7 human volunteers, using a specific radioimmuno-assay which measured both bezitramide and its active metabolite R-4618. A lag time of 0.5–1.0 h and a Cmax of 5.4 ng/ml plasma were found, the latter occurring 2.5–3.5 h after administration. The apparent elimination half-life varied from 11 to 24 h. Less than 0.3% of the dose was excreted unchanged in the urine. High concentrations in the faeces of some individuals indicate incomplete absorption and/or biliary secretion. The analgesic effect, using a standardized superficial electrical stimulation method, reached its maximum between 2.5 and 3.5 h after dosing, in accordance with the absorption phase. The duration of the effect was highly variable. Experiments in rats (n=6,3H-bezitramide 2.5 µg), demonstrated extensive biliary excretion (up to 70% of total radioactivity) and less than 3% of the label was removed by urinary excretion.
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