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  • 1
    Electronic Resource
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    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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    Entomologia experimentalis et applicata 69 (1993), S. 13-20 
    ISSN: 1570-7458
    Keywords: Artificial diets ; Coccinellidae ; rearing ; biological control ; Chilocorus spp. ; Coleoptera
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract Promising diets were screened and the most successful modified with additives used in artificial diets for other entomophagous insects. Two suitable diets were obtained, one for adults and one for larvae ofChilocorus nigritus (Fabricius) (Coleoptera: Coccinellidae). They were still inferior to natural prey and not adequate as the sole food source for rearing consecutive generations. They are valuable as substitute food in the insectary during shortages of natural prey. Oleander scaleAspidiotus nerii Bouché andAsterolecanium miliaris (Boisduval) were evaluated as natural prey forC. nigritus and two other potential biocontrol agents in southern Africa,C. bipustulatus (Linnaeus) andC. infernalis Mulsant.A. nerii andA. miliaris were suitable for all life stages ofC. nigritus and adults ofC. bipustulatus andC. infernalis. A. miliaris was inadequate for larvae ofC. bipustulatus andC. infernalis.
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  • 3
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    Entomologia experimentalis et applicata 68 (1993), S. 219-229 
    ISSN: 1570-7458
    Keywords: Hymenoptera ; Aphidiidae ; Homoptera ; Aphididae ; Schizaphis graminum ; wheat ; tritrophic interactions ; learning ; host-habitat location
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract The effect of experience on the responsiveness of the aphidiid parasitoidLysiphlebus testaceipes (Cresson) (Hymenoptera: Aphidiidae) to host-associated cues was investigated using a wind-tunnel bioassay. Naive females were able to discriminate between uninfested wheat (Triticum aestivum L.) and wheat infested withSchizaphis gramimum (Rondani) (Homoptera: Aphididae), but oviposition experience significantly increased the parasitoid's propensity to respond to aphid-infested plants with upwind, targeted flight. The behavioural change associated with such experience was acquired rapidly (within five minutes) and persisted for at least 24 h. The parasitoid could be successfully conditioned to associate a novel odour with the presence of hosts, suggesting that the increase in response to aphid-infested plants which occurs as a result of experience is probably due to associative learning of olfactory cues from the plant-aphid complex.
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  • 4
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    Entomologia experimentalis et applicata 66 (1993), S. 161-169 
    ISSN: 1570-7458
    Keywords: avoidance behaviour ; capture efficiency ; Coleoptera ; time-lapse video ; visual recording
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract Pitfall trap capture forSitophilus oryzae (L.),S. zeamais (Motschulsky),S. granarius (L.),Tribolium confusum (Duval),T. castaneum (Herbst);Oryzaephilus surinamensis (L.),Cryptolestes pusillus (Schonherr),Rhyzopertha dominica (Fabr.), andProstephanus truncatus (Horn) in millet was assessed by visual and time-lapse video recordings. The behaviour of different beetle species in arenas containing millet was monitored over 24 h and the frequency of encounters with the trap rim resulting in capture recorded. The capture efficiency of four types of pitfall traps (i.e. polystyrene, polythene, glass and tin-plated steel can) with rims exposed or submerged below the millet surface level were compared. Capture was related to beetle size, locomotory rate, and beetle behaviour at the trap rim as well as trap design and placement. The lighter and smaller species were least captured. Glass jars were more effective than plastic and metal containers. Traps placed with their rims submerged below the grain surface level were more efficient than those with rims exposed. Capture rate was unrelated to trap size. The frequency of encounters with trap rims was not correlated with capture rate. Three types of avoidance behaviours at the trap rims i.e. probing, skirting and spontaneous retreat, were related to capture rate, spontaneous retreat being the most effective escape mechanism and probing least.
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  • 5
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    Entomologia experimentalis et applicata 66 (1993), S. 191-196 
    ISSN: 1570-7458
    Keywords: Leptinotarsa decemlineata (Say) ; Coleoptera ; Chrysomelidae ; distribution ; diapause ; overwintering ; mortality
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
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  • 6
    ISSN: 1572-8889
    Keywords: Coleoptera ; Scarabaeidae ; Cotinis nitida (L.) ; beetle flight ; pheromone bioassay
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
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  • 7
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    Entomologia experimentalis et applicata 54 (1990), S. 219-224 
    ISSN: 1570-7458
    Keywords: Diabrotica virgifera virgifera ; Coleoptera ; Chrysomelidae ; corn ; life-stage occurrence ; planting date
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Description / Table of Contents: Résumé Dans les conditions de l'est du Sud Dakota (USA), 3 dates de semailles de maïs et 3 dates de contamination avec des œufs de D. virgifera virgifera LeConte ont servi à imposer ou à empêcher la synchronisation des éclosions des œufs et par conséquent des développements ultérieurs. Les dates médianes d'apparition de chacun des 3 stades larvaires et des imagos ont été déterminées en relation avec les unités de température et le nombre de jours depuis la contamination. Aucune différence significative entre les dates médianes d'apparition n'a été mise en évidence par utilisation des unités de température; par contre, ces différences deviennent significatives lorsque l'on utilise le nombre de jours depuis la contamination. Des paramètres fiables sont nécessaires pour prédire la présence des différentes stades de cet insecte. En dépit des différentes conditions imposées pour cette étude, la méthode la moins capricieuse pour prédire l'apparition d'un stade larvaire et l'émergence des adultes est la somme de températures avec une base de 11°C.
    Notes: Abstract Under field conditions in eastern South Dakota, USA three different planting dates of corn and three times of egg infestation were used to imposed synchronous and asynchronous timing of corn growth and Diabrotica virgifera virgifera LeConte egg hatch and subsequent development. Median occurrence of each of the three larval stages and of the adult stage for each of the infestation-planting treatments was determined by relating occurrence to thermal units and to days after infestation. No significant differences were found among the treatments for median occurrence of each life stage when the thermal unit approach was used. However, significant differences were found among treatments for median occurrence when the day after infestation approach was used. Consistent parameters are needed for prediction of the occurrence of life stages of this insect. Despite the various imposed conditions, this study indicates that the least variable method of predicting life stage occurrence and adult emergence of D. v. virgifera was the use of thermal unit accumulations (base 11°C).
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  • 8
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    Entomologia experimentalis et applicata 68 (1993), S. 9-13 
    ISSN: 1570-7458
    Keywords: bioassay ; behavioural response ; Coleoptera ; carob extract ; stored product
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract The behavioural responses ofCryptolestes pusillus Oryzaephilus surinamensis andProstephanus truncatus to different doses of carob extract were assessed in a two-choice pitfall bioassay and in plastic grain probe traps. The extract evoked a quick directional response and induced high beetle attraction to treated pitfall arenas compared with the controls. Overall, the extract improved probe trap efficiency by about 50% compared to unbaited probes. Beetle response was dose-dependent with the medium dose of 10 μl probably eliciting optimum response.
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  • 9
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    Cellular and molecular life sciences 46 (1990), S. 700-704 
    ISSN: 1420-9071
    Keywords: Coleoptera ; Tenebrionidae ; Tribolium confusum ; defesive secretion ; biosynthesis of 1-alkenes ; oxidative decarboxylation ; anti-elimination
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Summary The terminally unsaturated hydrocarbons of the defensive secretion ofTribolium confusum are biosynthesized from fatty acids by oxidative decarboxylation. The process involves an enantiospecific cleavage of the C−H bond of thepro-(S) C(3)−H atom and simultaneous decarboxylation of the acid into an 1-alkene and carbon dioxide via ananti-periplanar transition state geometry (anti-elimination). The stereochemistry of this biotranformation is identical in all respects with the same reaction in higher plants. The mechanism seems to be of general importance for the biosynthesis of many vinylic substructures of natural products from oxygen-containing precursors.
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  • 10
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    Cellular and molecular life sciences 49 (1993), S. 171-174 
    ISSN: 1420-9071
    Keywords: Coleoptera ; Meloidae ; Epicauta funebris ; chemical defense ; biosynthesis ; terpenoid
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract Cantharidin, a potent defensive chemical, is present in all ten life stages of the blister beetleEpicauta funebris. The first five larval stages accumulate cantharidin as they feed and grow in size. When disturbed, they exude cantharidin in a milky oral fluid, not in hemolymph which adult beetles reflexively discharge from leg joints. Two subsequent larval stages and the pupa do not feed, grow, regurgitate, or change in their defensive reserves (110 μg cantharidin/insect, regardless of sex). Adult beetles kept in isolation for 60–90 d exhibit a pronounced sexual dimorphism in cantharidin production: the male biosynthesizes about 17 mg of the toxin, representing 10% of his live weight, whereas the female actually loses most of her defensive reserves. But in the wild a female beetle repeatedly acquires cantharidin as copulatory gifts from her mates.
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  • 11
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    Cellular and molecular life sciences 49 (1993), S. 272-275 
    ISSN: 1420-9071
    Keywords: Semiochemical ; pheromone ; host selection ; competition ; Coleoptera ; Scolytidae
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract Bark beetles,Ips typographus andPityogenes chalcographus, attracted by synthetic or natural pheromone to Norway spruce logs,Picea abies, preferred to colonize uninfested logs rather than logs occupied by these beetles, probably as a means of avoiding intra-and interspecific competition. The aggregation pheromone components ofP. chalcographus, chalcogran and methyl (E, Z)-2,4-decadienoate, inhibited the attraction response ofI. typographus to its pheromone components (methyl butenol andcis-verbenol), while the converse was not true. However, verbenone released from colonized bark inhibited pheromonal response ofP. chalcographus.
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  • 12
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    Entomologia experimentalis et applicata 34 (1983), S. 291-296 
    ISSN: 1570-7458
    Keywords: Coleoptera ; Curculionidae ; Cyrtobagous ; Salvinia weevil ; Feeding characteristics of larvae ; Development of larvae ; Plant nutrition ; Temperature effects on development
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Description / Table of Contents: Résumé Après leur naissance, les larves de Cyrtobagous sp. passent de 1 à 4 jours à brouter les racines, et de 0 à 9 jours dans les bourgeons de la plante hôte, Salvinia molesta, avant d'y creuser une galerie dans le rhizome. Bien que les larves aient été capables de survivre jusqu'à 38 jours en broutant les racines, quant elles furent privées de rhizome, elle ne purent achever leur développement. Quand les galeries furent commencées, le développement larvaire, entre 21° et 31°, dépendit de la température et de la teneur en azote de l'hôte. Les larves ne se développèrent pas à 17°. Une haute valeur nutritive de l'aliment consommé par les larves réduisit la durée du développement, mais n'influença pas la durée ultérieure de leur développement nymphal. Les lieux de prise de nourriture et les dégâts produits par des larves isolées furent précisés.
    Notes: Abstract Newly-emerged larvae of a salvinia weevil, Cyrtobagous sp. spent from 1–4 days browsing on the roots and from 0–9 days in the buds of the host plant, Salvinia molesta, prior to tunnelling into the rhizome of this aquatic weed. Although larvae were able to survive up to 38 days browsing on roots when rhizomes were withheld, they were unable to complete development. After tunnelling began, larval development between 21° and 31° was dependent on temperature and nitrogen levels in the host. Larvae failed to develop at 17°. High nutritional intake by the larvae reduced larval development time but did not influence duration of their subsequent pupal development. The feeding sites and plant damage produced by individual larvae were assessed.
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  • 13
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    Entomologia experimentalis et applicata 56 (1990), S. 15-21 
    ISSN: 1570-7458
    Keywords: Coleoptera ; Chrysomelidae ; corn rootworms ; age-specific survival ; age-specific fecundity
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Description / Table of Contents: Résumé D. virgifera virgifera LeConte a été placé sur des régimes nutritifs mimant l'évolution des tissus du maïs disponsibles dans le champ lorsque les insectes éclosent est aux stades suivants du maïs: 1) après émergence de l'épi mâle, mais avant l'apparition des barbes et l'émission du pollen; 2) lors de la présence de barbes et de l'émission de pollen; 3) après la pollinisation et quand les barbes ont bruni. Un quatrième régime a été fourni pendant toute l'expérience comprenant des barbes vertes, du pollen et des feuilles. Les pontes moyennes des femelles pendant les 12 semaines de l'étude on été 125, 235, 179 et 441 pour les régimes 1, 2, 3 et 4. Les dates de mort de la moitié des adultes a été 7,2, 7,2, 6,7 et 8,8 semaines pour respectivement les mêmes régimes. Les femelles du régime 1 pondent à un âge plus avancé que les femelles des régimes 2 et 3. L'influence des changements de la qualité alimentaire du maïs au fur et à mesure du vieillissement des plantes et deDiabrotica, a été déterminée par la survie au bout de 48 heures d'insectes éclos depuis peu et d'autres maintenus en cage sur des lots de maïs à différents stades poussant en serre depuis des temps plus ou moins longs. Plus les plantes sont âgées, plus la survie des 2 groupes deDiabrotica diminue, mais plus vite chez les lots d'insectes âgés.
    Notes: Abstract Adult corn rootworm beetles,Diabrotica virgifera virgifera LeConte, were maintained on three dietary regimes which mimicked the progression of corn tissues that would be available in the field for beetles eclosing when corn was in the following growth stages: (A) after tassels had emerged but prior to silking and pollen shed; (B) while plants were silking and shedding pollen; and (C) after pollination was complete and silks had turned brown. A fourth regime (D) was established in which green corn silks, pollen, and leaves were provided throughout the study. The mean number of eggs laid per female over the 12-week duration of the study was 125, 235, 179, and 441 for regimes A, B, C, and D, respectively. Median length of life was 7.2, 7.2, 6.7, and 8.8 weeks for regimes A, B, C, and D respectively. Beetles in regime A laid a greater proportion of their eggs at an older age than did beetles from regimes B and C. To further investigate the influences on survival of changes in food quality of corn as plants and beetles aged, newly-eclosed beetles and beetles that had been maintained in caged plots of corn growing in a greenhouse for various lengths of time were caged on corn at different stages of growth, and the proportion of beetles surviving for 48 h was determined. Survival decreased as plants aged for both groups of beetles, but decreased at a faster rate for old than for young beetles.
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  • 14
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    Entomologia experimentalis et applicata 34 (1983), S. 124-126 
    ISSN: 1570-7458
    Keywords: Negret ; Melanic mutant ; X-linked mutation ; Flour Beetle ; Tribolium confusum ; Coleoptera
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
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  • 15
    ISSN: 1570-7458
    Keywords: Storage pests ; Coleoptera ; Bostrichidae ; Prostephanus truncatus ; (±)-1-methylbutyl (E)-2-methyl-2-pentenoate ; Rhyzopertha dominica ; (±)-1-methyl-butyl (E)-2,4-dimethyl-2-pentenoate ; Dominicalure ; Aggregation pheromone ; Monitoring
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Description / Table of Contents: Résumé Les réponses de Prostephanus truncatus Horn (Coleoptera: Bostrichidae) à deux constituants de la phéromone d'agrégation de Rhyzopertha dominica Fabricius (Coleoptera: Bostrichidae), le (±)-1-méthylbutyl (E)-2-méthyl-2-penténoate et le (±)-1-méthylbutyl (E)-2,4-diméthyl-2-pentéoate, connus comme “Dominicalure 1” et “Dominicalure 2”, ont été étudiées au laboratoire et au champ. Auslaboratoire ces composés ont été essayés individuellement et en mélange 1:2. Une membrane de caoutchouc imprégnée de phéromone a été utilisée comme émetteur lent, et une courbe de réponse en fonction de la dose a été établie. P. truncatus répondait plus vigoureusement à la Dominicalure 2 seule. Tous ces traitements ont été comparés dans un essai aux champs en Tanzanie, dans lesquels des pièges en carton ondulé contenant des diffuseurs de phéromone étaient placés dans des entrepôts de maïs dans les fermes. La Dominicalure 1 et le mélange de 1 et 2 étaient tous deux efficaces pour piéger R. dominica. La Dominicalure 2 a piégé plus de P. truncatus que les autres traitements et était à peu près aussi efficace que le contrôle visuel pour détecter la présence de cet insecte dans les stocks. On peut envisager que la Dominicalure 2 pourrait servir de base à un programme pour lutter contre P. truncatus en Afrique de l'Est.
    Notes: Abstract Laboratory and field studies have been made of the responses of Prostephanus truncatus (Horn) to two components of the aggregation pheromone of Rhyzopertha dominica (Fabricius) — (±)-1-methylbutyl (E)-2-methyl-2-pentenoate and (±)-1-methylbutyl (E)-2,4-dimethyl-2-pentenoate, known as “Dominicalure 1” and “Dominicalure 2” respectively. In the laboratory, these compounds were tested individually and as a 1:2 mixture; P. truncatus responded most strongly to Dominicalure 2 alone. All three treatments were compared in a field trial in Tanzania to monitor both R. dominica and P. truncatus in farm stores. Dominicalure 1 or a mixture of 1 and 2 were both highly effective for trapping R. dominica. In contrast, Dominicalure 2 trapped more P. truncatus than the other treatments and was about as effective as visual inspection at demonstrating the presence of the beetle in stores. Dominicalure 2 could form the basis of a monitoring programme for P. truncatus in East Africa.
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  • 16
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    European journal of nutrition 22 (1983), S. 27-33 
    ISSN: 1436-6215
    Keywords: wheat ; lysine ; carnitine ; lipids ; mitochondria
    Source: Springer Online Journal Archives 1860-2000
    Topics: Agriculture, Forestry, Horticulture, Fishery, Domestic Science, Nutrition , Medicine
    Description / Table of Contents: Zusammenfassung 32 abgesetzte männliche Albinoratten wurden in 4 Gruppen eingeteilt, um die Wirkung einer lysinarmen Weizendiät (AW), einer Weizendiät mit 0,4 % Lysin (LW) oder 0,2 % Carnitin (CW) sowie einer Caseindiät auf den Stoffwechsel von Lipiden in verschiedenen Geweben zu untersuchen. Nach 8 Wochen Fütterung der verschiedenen Diäten unter Anwendung der „paired feeding technique“ wurden Veränderungen in den Gesamtlipiden, den Lipidbestandteilen, den einzelnen Fettsäuren und dem Lipidgehalt der Mitochondrien des Herzens, der Skelettmuskeln, der Lungen und des Fettgewebes der Tiere bestimmt. Die lysinarme Weizendiät (AW) bewirkte eine Lipidanreicherung (vor allem an Acylglyzerinen) im Herzen, in der Leber, den Skelettmuskeln sowie eine Lipidabnahme im Fettgewebe. Die Diäten mit 0,4 % Lysin (LW) oder 0,2 % Carnitin (CW) zeitigten die entgegengesetzte Wirkung, wobei CW wirkungsvoller erschien als LW. LW und CW erhöhten die relativen Anteile von C14∶0-, C16∶0- und C16∶1-Fettsäuren und verkleinerten diejenigen von C18∶1-, C18∶2- und C18∶3-Fettsäuren, während die Anteile unter der AW- und Caseindiät ab- bzw. zunahmen. Die Fettsäurezusammensetzung des Fettgewebes war bei allen Gruppen gleich. Die AW-Diät vergrößerte die relativen Anteile von C14∶0- und C20∶4- und verringerte die von C16∶0-, C16∶1- und C18∶3-Fettsäuren in den Lungen. Die AW-Ergänzungsdiäten verringerten die relativen Anteile von C16∶0-, C16∶1-, C18∶3-sowie auch der C18∶1-Fettsäuren. Der Lipidgehalt der Mitochondrien von Leber, Herz, Skelettmuskeln und Lunge verringerte sich unter der AW-Diät und erhöhte sich unter den LW- und CW-Diäten.
    Notes: Summary 32 weanling male albino rats were divided into 4 groups to study the effects of lysine-deficient wheat diet (AW) and AW supplemented with either 0.4 % lysine (LW) or 0.2 % carnitine (CW) as compared to casein diet on metabolism of lipids in various tissues. LW, CW and casein diet groups were pair-fed with AW group. Changes in total lipids, lipid components, individual fatty acids, mitochondrial content in liver, heart, skeletal muscles, lungs and adipose tissue were determined after 8 weeks of feeding. AW diet resulted in accumulation of lipids (mainly acylglycerols) in heart, liver, skeletal muscles and depletion in adipose tissue. The LW and CW diets reversed the effects of AW diet, the CW being more effective than LW diet. The LW and CW diets increased the relative proportion of C 14∶0, C 16∶0, C 16∶1 and decreased that of C18∶1, C18∶2, C18∶3 fatty acids which were decreased and increased, respectively, on the AW and casein diets. The fatty acids composition of adipose tissue was the same in all the groups. The AW diet increased the relative proportions of C 14∶0, C 20∶4 and decreased that of C 16∶0, C 16∶1, C 18∶3 fatty acids in the lungs. Supplemented AW diet decreased the relative proportions of the former group and increased that of the later group including C 18∶1 fatty acid also. The mitochondrial content of liver, heart, skeletal muscles and lungs was decreased on AW and reversed on LW and CW diets.
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  • 17
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    Mycopathologia 111 (1990), S. 181-189 
    ISSN: 1573-0832
    Keywords: mycotoxin ; ochratoxin ; Penicillium ; storage ; wheat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract Eleven-kilogram parcels of HY-320 wheat, a cultivar of the new Canada Prairie Spring class, were kept at 15 and 19% initial moisture contents (IMC) in simulated storage in a Manitoba farm granary for 60 weeks to determine biotic and abiotic changes and mycotoxin production. Ochratoxin A reached a maximum of 0.24 ppm by week 20 in the 19% IMC wheat, but was absent in the 15% IMC wheat; no other mycotoxins were detected. Temperature, moisture content, O2 and CO2 levels, fat acidity values, seed germination, microfloral incidence and abundance, and the presence of other mycotoxins were monitored. Principal component analysis of all variables showed that the first principal components accounted for 32–41% of the system variability, and contained the ochratoxin A variable. Ochratoxin A was produced in moist grain that had decreased seed germination andAltermaria activity, and high fungal activity byPenicillium andAspergillus versicolor. Compared to other stored cereals previously studied, HY-320 wheat would be ranked in a low-risk category for mycotoxin formation, based on the ochratoxin A levels observed.
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  • 18
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    Nutrient cycling in agroecosystems 21 (1990), S. 163-166 
    ISSN: 1573-0867
    Keywords: Critical level of Zn ; alkaline soils ; Zn-deficiency ; wheat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Agriculture, Forestry, Horticulture, Fishery, Domestic Science, Nutrition
    Notes: Abstract Field experiments were conducted at 32 locations, chosen for their wide range in DTPA extractable Zn, to determine the critical deficiency level of Zn for predicting response of wheat to Zn application. Soil application of 5.6 kg Zn ha−1 significantly increased the grain yield in deficient soils. Soil extractable Zn was significantly related with per cent grain response and absolute grain yield. Both the graphical and statistical methods of Cate and Nelson indicated the critical level to be 0.75 mg kg−1 soil of DTPA extractable Zn. This level gave a predictability value of 82 per cent.
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  • 19
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    Nutrient cycling in agroecosystems 22 (1990), S. 147-159 
    ISSN: 1573-0867
    Keywords: Sulfate ; elemental sulfur ; leaching ; ryegrass ; wheat ; greenhouse experiments ; split application
    Source: Springer Online Journal Archives 1860-2000
    Topics: Agriculture, Forestry, Horticulture, Fishery, Domestic Science, Nutrition
    Notes: Abstract Three factorial experiments with four replications were conducted in a greenhouse to examine the effectiveness of gypsum, elemental sulfur (ES powder) and three S containing N fertilizers, viz., ammonium sulfate (AS), urea + ES, and Ureas (20% AS and 80% urea). All experiments were conducted twice in different years. In the first experiment with uncropped soil, the effects of soil type, leaching rate (2.3 and 6.9 mm water per day) and urea addition on sulfate leaching losses were studied. Leaching losses decreased in the order Ureas 〉 ammonium sulfate (AS) 〉 gypsum ≫ urea + ES. Increasing the leaching rate greatly increased sulfate losses from both soils. Losses were greater in the sandy Typic Hapludoll than in the clayey Oxic Paleustalf. Sulfate adsorption was found to decrease strongly with rising the pH in both soils. Hydrolysis of urea temporarily raised the pH of the soil, thereby increasing the sulfate leaching losses. In the second experiment the effects of S rate (0–65 mg per kg soil), split application and leaching rate (0 and 2.3 mm per day) on sulfate leaching losses and ‘apparent S recovery’ (ASR) by three successive cuts of ryegrass (Lolium perenne L.) were studied. Herbage yield more than doubled when S was applied. The effectiveness of the sulfate fertilizers was greater when S was split-applied than given all at once. With split applications the ASR decreased in the order: Ureas 〉 AS 〉 gypsum 〉 urea + ES 〉 ES powder. ES fertilizers were least effective, because the oxidation rate of ES to sulfate was clearly too slow. In the third experiment the effects of S rate (0–40 mg per kg soil) and split application on sulfate leaching losses and ASR in the grain of wheat (Triticum aestivum L.) were studied under leaching conditions (2.3 mm per day). Grain yield increased strongly due to S application. Split application greatly increased the effectiveness of the sulfate fertilizers and appeared to be an effective tool in satisfying the S need of the crop under leaching conditions. Again, ES fertilizers were least effective, because the oxidation rate of ES was too slow to meet the S demand of the crop. In all experiments leaching losses of sulfate from the ES fertilizers were smaller than from the sulfate fertilizers.
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  • 20
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    Nutrient cycling in agroecosystems 22 (1990), S. 97-107 
    ISSN: 1573-0867
    Keywords: Superphosphate ; placement depth ; banding ; relative effectivenesss ; lupins ; wheat ; field experiment
    Source: Springer Online Journal Archives 1860-2000
    Topics: Agriculture, Forestry, Horticulture, Fishery, Domestic Science, Nutrition
    Notes: Abstract In a field experiment on a sandplain soil in a low rainfall (326mm per annum) Mediterranean environment of south-western Australia, seven levels of single superphosphate, 0, 7.5, 10, 14, 19.5, 30 and 39 kg P ha−1, were placed at either 3, 5, 7, 9, 11 or 13 cm depth before sowing wheat (Triticum aestivum) at 3 cm. In a separate treatment, superphosphate was drilled with the seed (the normal practice). In the second year, the plots were sown with lupins (Lupinus angustifolius) at 3 cm depth with no additional superphosphate. In three separate treatments, superphosphate at 0, 14 and 39 kg P ha−1, was drilled with the lupin seed (the normal practice) on plots that had received no superphosphate in the first year. Yields of wheat and lupins were used as a measure of the effectiveness of the superphosphate placement treatments relative to the effectiveness of superphosphate drilled with seed of wheat (year 1) or lupins (year 2), to give relative effectiveness (RE) values in each of the two years. In the first year the RE of superphosphate was increased by about 20% when the fertilizer was placed 5 to 9 cm deep in the soil. In the second year, the RE of superphosphate for producing lupin grain was increased by about 30–60% where the fertilizer had been placed 5–13 cm deep in the previous year compared with freshly drilled 3 cm deep. The yield of wheat or lupins was closely related to the P content of plant tissue; each relationship was independent of the depth or year of superphosphate application.
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  • 21
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    Nutrient cycling in agroecosystems 26 (1990), S. 229-235 
    ISSN: 1573-0867
    Keywords: Grass ; wheat ; nitrogen nutrition ; dilution curve ; mineral content ; mineral removal ; phosphorus ; potassium
    Source: Springer Online Journal Archives 1860-2000
    Topics: Agriculture, Forestry, Horticulture, Fishery, Domestic Science, Nutrition
    Notes: Abstract The important effect of nitrogen in changing the patterns of mineral content and mineral removal is analysed for grass swards and wheat. Different models are proposed; accumulated dry matter developed throughout a growing period is shown to be an excellent reference for assessing the evolution of the plant mineral content and the mineral removal the growing crop. Applications in diagnosing mineral nutrition status and optimising fertilizer use are proposed and discussed.
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  • 22
    ISSN: 1423-0445
    Keywords: toxin sequestration ; predation ; human dietary hazard ; cantharidin ; Coleoptera ; Meloidae ; Epicauta vittata ; Rana ; Hirudo ; Nerodia
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary Frogs(Rana pipiens) fed on blister beetles (Meloidae) or cantharidin, retain cantharidin systemically. After cessation of feeding, they void the compound relatively quickly. Systemic cantharidin does not protect frogs against ectoparasitic feeding by leeches(Hirudo medicinalis) or predation by snakes(Nerodia sipedon). As suggested by our data, and from reports in the early literature, ingestion of cantharidin-containing frogs can pose a health threat to humans.
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  • 23
    ISSN: 1423-0445
    Keywords: pheromone ; attractant ; triene ; tetraene ; hydrocarbon ; Insecta ; Coleoptera ; Nitidulidae ; Carpophilus freemani
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary Males ofCarpophilus freemani Dobson (Coleoptera: Nitidulidae) produce an aggregation pheromone to which both sexes fly in a wind-tunnel bioassay. The major pheromone component (ca. 30 ng per male per day in volatile collections) was identified as (2E,4E,6E)-5-ethyl-3-methyl-2,4,6-nonatriene. A minor component, (2E,4E,6E,8E)-7-ethyl-3,5-dimethyl-2,4,6,8-undecatetraene, was 3–10% as abundant as the major triene and was 5–20% as active when compared at relative doses ranging from natural proportions to 1:1. These compounds act synergistically: a mixture of major and minor components in natural proportions attracted more than twice as many beetles as the major component alone, and the mixture fully accounted for the activity of male-derived volatile collections. Six other male-derived conjugated hydrocarbons, ranging from 2% down to 0.04% as abundant as the major component, were also identified. These are (in order of decreasing bioassay activity when compared on an equal-weight basis): (3E,5E,7E)-6-ethyl-4-methyl-3,5,7-decatriene, (2E,4E,6E)-5-ethyl-3-me-thyl-2,4,6-octatriene, (3E,5E,7E,9E)-8-ethyl-4,6-dimethyl-3, 5,7,9-dodecatetraene, (2E,4E,6E,8E)-3,5,7-trimethyl-2,4,6, 8-undecatetraene, (3E,5E,7E)-5-ethyl-7-methyl-3,5,7-undecatriene, and (2E,4E,6E)-3,5-dimethyl-2,4,6-nonatriene. All structure identifications were confirmed by synthesis. In the wind tunnel, the pheromone acted synergistically with “host”-type volatiles such as propyl acetate, valeric acid, and ethanol. This concept was verified by fields tests in California, in which there was dramatic synergism between the pheromone and fermenting host materials. Pheromone biosynthesis is discussed.
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  • 24
    ISSN: 1423-0445
    Keywords: secretion-grooming ; pygidial glands ; chemical defence against microorganisms ; respiration ; aquatic beetles ; Coleoptera ; Hydradephaga ; Gyrinidae ; Haliplidae ; Noteridae ; Hygrobiidae ; Dytiscidae
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary All Hydradephaga investigated so far crawl onto land when exposed to an increase in water temperature and light intensity and spread the secretion from their pygidial glands over the body surface (“secretion-grooming”). The secretions have antimicrobial properties and are mainly applied to hydrofuge body regions important for aquatic respiration. Experimental prevention of secretion-grooming leads to the loss of the respiratory air bubble and a significant increase in mortality. These findings support the view that the secretion-grooming of adephagous aquatic beetles, like in some aquatic Heteroptera, inhibits the growth of microor-ganisms, thus preventing the contamination and wetting of the cuticular respiratory structures. Thus it keeps functional the air-retaining hydrophobous body regions essential for aquatic respiration. A model is presented on how secretion-grooming may have evolved in the Hydradephaga. Other possible functions of the pygidial gland secretions are discussed.
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  • 25
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    Chemoecology 4 (1993), S. 29-32 
    ISSN: 1423-0445
    Keywords: chemical defence ; alkaloids ; predation ; Coleoptera ; Coccinellidae ; Adalia bipunctata ; Coccinella septempunctata ; Hymenoptera ; Formicidae ; Lasius niger
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract Garden black ants,Lasius niger L., in a laboratory colony, attacked three species of live ladybirds found near their nest, killing the smaller two species. A second colony was offered artificial diets containing crushed ladybirds of two species, and the ants' choice of feeding site noted. Both the diets were aversive compared to control, but that containing 7spot,Coccinella septempunctata L., was more aversive than the diet containing 2spot,Adalia bipunctata L. The implications of this lesser protection for 2spots in terms of the chemical defence of the species are discussed.
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  • 26
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    Cellular and molecular life sciences 46 (1990), S. 1016-1017 
    ISSN: 1420-9071
    Keywords: In vitro absorption ; calcium ; wheat ; Bengal gram
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Summary The in vitro absorption of calcium from the duodenum was significantly less in a group of rats fed on a wheat diet than in a group fed a wheat and Bengal gram (70∶30) diet.
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  • 27
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    Cellular and molecular life sciences 46 (1990), S. 1209-1211 
    ISSN: 1420-9071
    Keywords: Pheromone ; E-myrcenol ; ipsdienol ; Ips duplicatus ; Coleoptera ; Scolytidae ; Picea abies
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Summary Males of the Eurasian bark beetleIps duplicatus, when feeding in host Norway spruce (Picea abies (L.) Karst.), produced and released ipsdienol andE-myrcenol, which we show to be aggregation pheromone components. Bioassays using walking beetles indicated thatE-myrcenol in synergistic combination with ipsdienol is essential for attraction. Synergism ofE-myrcenol and ipsdienol released at natural rates in the forest was also demonstrated with a new technique using mechanical slow-rotation of sticky traps.
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  • 28
    ISSN: 1423-0445
    Keywords: chemical defense ; predator-prey interaction ; synergism ; Coleoptera ; Staphylinidae ; Oxytelinae ; Bledius ; Carabidae ; Dyschirius ; Pogonus ; Dichirotrichus ; Formicinae ; Cataglyphis ; Dermaptera ; Labidura
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary The adaptation of defensive secretions to their target organisms was examined for the abdominal gland secretions ofBledius furcatus, B. spectabilis andB. arenarius. Therefore the target organisms of the secretion of theseBledius species (i.e. their predators) had to be identified. At the collection sites examined these were the earwigLabidura riparia, the antCataglyphis bicolor, the flyLispe candicans, different carabids of the generaPogonus, Dichirotrichus, Dyschirius, Bembidion andCalathus and the wading birdsHaematopus ostralegus andCalidris alba. The secretion of the abdominal glands contains the toxin ptoluquinone dissolved in eitherγ-dodecalactone and 1-undecene (B. furcatus andB. spectabilis) or in octanoic acid and octyloctanoate (B. arenarius). The ratio of these solvents is species-specific. Application experiments using some of the natural insect predators (L. riparia, C. bicolor, Pogonus, Di. gustavii, Dyschirius) revealed that these solvent ratios provided a more effective deterrent than other possible ratios. Thus by combining the solvents in certain ratios, the capability of cuticular penetration and therefore the effectiveness of the defensive secretions are adapted to their natural targets.
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  • 29
    ISSN: 1432-1939
    Keywords: Coleoptera ; Herbivory ; Host selection ; Maternal effect ; Paternal effect
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract The natural host of Ophraella notulata is Iva frutescens (Asteraceae); its close relative feeds on a related plant, Ambrosia artemisiifolia. We reared beetles on both plants, obtained progeny from the four possible crosses (two sexes X two parental hosts), and reared the progeny on both plant species. Survival to the imaginal stage of progeny reared on Iva varied with both maternal and paternal host. Hatchling feeding response to both plants showed a maternal host X paternal host interaction. Consumption of Ambrosia by adult beetles was, counter to expectation, higher for progeny of Iva-reared males than Ambrosia-reared males. Oviposition response, although based on too few data to be definitive, was peculiar: parental host did not affect oviposition on Ambrosia; on Iva daughters of Iva-reared males laid significantly more eggs than did daughters of Ambrosia-reared males, but only if they had been reared on Iva; those reared on Ambrosia displayed the reverse pattern. We discuss the possibility that nongenetic paternal transmission of host plant effects may explain these results, but offer a somewhat uncomfortable hypothesis of selection as a preferable explanation. An important outcome of the experiment is that it provided no evidence of maternal effects of host plant on offspring feeding or oviposition.
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  • 30
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    European journal of clinical pharmacology 39 (1990), S. 395-397 
    ISSN: 1432-1041
    Keywords: atropine ; exercise ; pharmacokinetics ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Seven healthy males (19–32 y) underwent each of four separate conditions in a repeated measures design. Five of these subjects underwent an additional trial. In four of five trials subjects received 2.0 mg atropine sulfate intramuscularly in the anterolateral portion of the left thigh: at rest (T1); following completion of a single exercise (Ex) bout (T2), (Each bout consisted of 25 min of stationary cycling at 40% VO2 max with 5 min of seated rest), prior to three Ex bouts (T3) and following one and prior to three Ex bouts (T5). Trial 4 (T4) was the same as T3 with the substitution of a saline placebo. Serum samples were collected over a 12 h period and atropine concentration was determined by RIA. Ex trials were compared to T1. Ex prior to atropine (T2) significantly decreased the mean volume of distribution (Vz, 278 vs 2321). Ex in T3 significantly decreased the serum half life (t1/2, 4.2 vs 3.5 h), Vz (278 vs 1981), and clearance (CL, 763 vs 638 ml·min−1) and significantly increased the peak concentration (Cp, 6.7 vs 12.3 ng·ml−1) and area under the curve (AUC, 44.1 vs 53.1 ng·ml−1). In T5, Ex significantly decreased the t1/2 (3.4 h), Vz (182 l) and CL (575 ml·min−1) and significantly increased the absorption rate constant (ka, 0.482 vs 1.1 min−1), elimination rate constant (ke, 0.0012 vs 0.0015 min−1), Cp (14 ng·ml−1) and AUC (53.3 ng·h·ml−1). These results demonstrate that moderate Ex either prior to and/or immediately following drug administration has the capacity to significantly modify atropine pharmacokinetics.
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  • 31
    ISSN: 1432-1041
    Keywords: Liver cirrhosis ; Spirapril ; ACE inhibitor ; pharmacokinetics ; haemodynamic effects ; liver function tests
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics and haemodynamic effects of orally administered spirapril, a novel angiotensinconverting enzyme (ACE) inhibitor, have been investigated in patients with liver cirrhosis (n=10), in patients with chronic, non-cirrhotic liver disease (n=8) and in a control group of healthy subjects (n=16). The absorption and elimination of spirapril did not differ between patients with liver disease and control subjects. In contrast, the bioavailability of spiraprilat, the metabolite responsible for the pharmacological action of spirapril, was significantly reduced in patients (AUC 820 μg·h·l−1, 923 μg·h·l−1 and 1300 μg·h·l−1 in patients with cirrhosis, patients with non-cirrhotic liver disease and in healthy subjects, respectively. Compared to healthy subjects, cirrhotic patients had a reduced rate constant of spiraprilat formation (1.10 h−1 in patients vs. 2.00 h−1 in control subjects) while the elimination half-life of spiraprilat was not different. The effect of spirapril on diastolic blood pressure was decreased in patients with chronic liver disease as compared to the controls. Thus, the pharmacokinetics of spirapril was unchanged in patients with different types of liver disease, including cirrhosis. However, the bioavailability of spiraprilat and hypotensive effect of spirapril were reduced in patients.
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  • 32
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    European journal of clinical pharmacology 45 (1993), S. 357-361 
    ISSN: 1432-1041
    Keywords: Circadian rhythms ; Indomethacin ; Ketoprofen ; pharmacokinetics ; time-varying models ; nonsteroidal anti-inflammatory drugs
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary A one-compartment model with first-order absorption has provided good fits to five sets of indomethacin data and four sets of ketoprofen data taken at different times of day. There was substantial variation in the model parameters with time of administration and most of the features of this variation applied equally to both drugs. From the data examined, the source of variation appears to be mainly in the absorption phase and this was confirmed using a chronokinetic analysis, in which simultaneous fits were obtained with time-variant rate parameters. However, there may also be circadian variation in protein binding. The danger of quoting parameter values for either of these two drugs based on administration at a single time of day has been illustrated, and this may well be true for other drugs.
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  • 33
    ISSN: 1432-1041
    Keywords: Gamma-hydroxybutyric acid ; pharmacokinetics ; dose-proportionality
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Gamma-hydroxybutyric acid (GHB) is effective in treatment of the alcohol and opiate withdrawal syndromes. Its absorption and disposition kinetics have been studied in 8 healthy male volunteers following oral administration of single doses of 12.5, 25 and 50 mg kg−1. The AUC increased disproportionately with the dose and so the apparent oral clearance decreased significantly as the dose was increased, whereas the terminal half-life and mean residence time increased. The peak plasma concentrations normalised to the lowest dose fell significantly with increasing doses, whilst the corresponding peak times increased. These findings suggest that both the oral absorption and the elimination of GHB are capacity-limited processes. GHB did not bind to significant extent to plasma proteins over the therapeutic concentration range. The pharmacokinetic parameters in healthy volunteers were not significantly different from those previously observed in alcohol-dependent patients with compensated alcoholic liver disease.
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  • 34
    ISSN: 1432-1041
    Keywords: Glyceryl trinitrate spray ; pharmacokinetics ; a/b-ratio ; pulmonary artery diastolic pressure ; finger pulse curve ; bioavailability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The time course and the magnitude of the effect of glyceryl trinitrate (GTN) on central venous (pulmonary artery diastolic pressure-PAPd) and peripheral arterial (a/b-ratio of the finger pulse wave) haemodynamics were compared in a randomized double-blind cross-over study in 12 patients suffering from congestive heart failure (NYHA II–III) with elevated PADd at rest (≥15 mm Hg). The data were obtained in a bioavailability study of two sprays of glyceryl trinitrate, which differed in their galenical characteristics and in the dose of GTN (0.4 mg vs. 0.8 mg). Following sublingual administration of each spray, PAPd, a/b-ratio and the plasma concentrations of GTN and its metabolites were measured up to 30 min. The relative bioavailability of GTN of the test preparation was estimated to be 157%, 161% and 147%, when calculated from the plasma concentration-time data or the integrated effect of GTN on a/b-ratio or PAPd, respectively. The mean time courses of the decrease in PAPd and the increase in the a/b-ratio of the finger pulse curve were mirror images. Thus, there was a strong correlation between the mean values of PAPd and a/b-ratio following the administration of glyceryl trinitrate. Since the slope of the relationship differed considerably between the patients, the magnitude of effect of GTN on PAPd in the individual patient could not be predicted from the changes in a/b-ratio.
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  • 35
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    European journal of clinical pharmacology 44 (1993), S. 463-466 
    ISSN: 1432-1041
    Keywords: Benazepril ; Proteinuria ; benazeprilat ; ACE inhibitor ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary We have investigated whether the pharmacokinetics and pharmacodynamics of the ACE inhibitor benazepril hydrochloride are altered with proteinuria by studying 8 patients with major proteinuria of different causes who were given a single dose of 10 mg p.o. The maximum plasma concentration of benazepril was found between 0.5 and 2 h after dosing (median 1 h). Its elimination was almost complete within 6 h. Peak plasma levels of benazeprilat, the active metabolite of benazepril, were observed between 1 and 6 h (median 2.5 h). The elimination of benazeprilat from plasma was biphasic, with mean initial and terminal half-lives of 3.0 and 17.3 h, respectively. On average, the pharmacokinetic parameters of benazepril and benazeprilat in the patients did not differ from those in a historical control group of healthy volunteers, but intersubject variability in the AUC and half-lives of benazeprilat was greater in the patients. Plasma ACE was completely inhibited from 1.5 to 6 h after dosing, and at 48 h the mean inhibition was still 42 %. Plasma renin showed substantial intersubject variation. Mean supine blood pressure (systolic/diastolic) was reduced from baseline by a maximum of 18/13 mm Hg at 6 h. Proteinuria was diminished after benazepril in 7 patients. In conclusion, the results of this study suggest that proteinuria in the nephrotic range does not require a change in benazepril dosage.
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  • 36
    ISSN: 1432-1041
    Keywords: dDAVP ; bioavailability ; gastrointestinal tract ; healthy volunteers ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The absolute bioavailability of an aqueous solution of 1-deamino-8-D-arginine vasopressin (dDAVP) from different regions of the gastrointestinal (GI) tract (stomach, duodenum, jejunum, ileum, colon, rectum) has been studied in 6 healthy, male volunteers aged 24 to 35 years, followed for 12 h after each drug administration. For i. v. administration the subjects received 4 μg dDAVP. For intestinal administration 400 μg dDAVP was directly applied to six distinct sites in the GI tract via two or four channel tubes with or without a distal occlusive balloon. Biological effects were assessed and plasma and urinary levels of dDAVP were measured using a specific, sensitive RIA. Urine osmolality remained elevated and diuresis decreased for 12 h following dDAVP administration irrespective of the site of application. After i. v. administration, the half-life of elimination of dDAVP was 60.0 min, plasma clearance 1.7 ml·min−1·kg−1, amount excreted in urine 2.0 μg and renal clearance was 0.8 ml·min−1·kg−1. The mean bioavailability (f) after gastric application was 0.19% (range 0.02–0.35%). f was 0.24% after duodenal application (range 0.04–0.62%), 0.19% after jejunal (range 0.01–0.41%), 0.03% after distal ileal (range 0.01–0.08%), 0.04% after proximal colonic (range 0.01–0.12%) and 0.04% after rectal (0.01–0.10%) application. The bioavailability was significantly higher in the three upper GI regions in comparison to the three lower regions. The bioavailability of dDAVP after gastric, duodenal and jejunal application was similar to that after swallowing a tablet in a previous study. Absorption from the ileum was lower than expected and no preferential site of absorption was found.
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  • 37
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    European journal of clinical pharmacology 44 (1993), S. 247-251 
    ISSN: 1432-1041
    Keywords: Proguanil ; Pregnancy ; Malaria ; cycloguanil ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Plasma and whole blood concentrations of proguanil, its active metabolite cycloguanil, and the inactive metabolite 4-chlorophenyl-biguanide, were measured by HPLC in 10 healthy Karen women in the last trimester of pregnancy, following a 200 mg single oral dose of proguanil. Four of these women were restudied 2 months after delivery. The pharmacokinetic properties of proguanil were similar during and after pregnancy. Median peak plasma concentrations of proguanil during pregnancy and following delivery were 212 and 215 ng·ml−1, and occurred at 4.5 and 5 h, respectively. Mean plasma AUC values for proguanil during and following pregnancy were 94 and 98 ng·h·ml−1·kg−1, respectively. Corresponding whole blood AUC values were 361 and 396 ng·h·ml−1·kg−1. The mean elimination half lives and mean residence times of proguanil in plasma and whole blood were 12.3 and 19.6 h and 13.8 and 20.7 h respectively during pregnancy. Following pregnancy these values were 17.1 and 19.7 h for plasma and 19.7 h and 20.2 h for whole blood respectively. Mean peak plasma and whole blood concentrations of cycloguanil following pregnancy were 25 and 22 ng·ml−1 respectively. During pregnancy peak cycloguanil concentrations in both plasma and whole blood were markedly lower, 13 and 12 ng ml−1, respectively. Two pregnant women (neither of whom were restudied) were probably poor metabolisers of proguanil. The mean ratio of proguanil to cycloguanil plasma AUC was 16.7 in the third trimester of pregnancy and 7.8 following pregnancy, compared with less than 5 in previously reported studies. The concentrations of 4-chlorophenylbiguanide in both plasma and whole blood in pregnant subjects were also lower than those after pregnancy. These data show that blood concentrations of the active antimalarial metabolite cycloguanil are reduced in late pregnancy and that the currently recommended dose of proguanil could be inadequate for antimalarial prophylaxis in pregnant women.
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  • 38
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    European journal of clinical pharmacology 44 (1993), S. 265-269 
    ISSN: 1432-1041
    Keywords: Cyclosporine ; Renal transplantation ; pharmacokinetics ; intraindividual variation ; circadian variation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The intraindividual variability and circadian variation of oral cyclosporine (CsA) pharmacokinetics were studied over 24 h in 18 renal transplant recipients at steady state, and in 10 of the patients during a second 24 h period. The absolute percentage intraindividual difference in daytime AUC (0–12 h) ranged from 2% to 54% (mean 30%), and the corresponding variability in nighttime AUC (0–12 h) ranged from 5% to 80% (mean 34%). The pharmacokinetic variables t1/2, tmax and Cmax were more variable than the AUC (0–12 h) both during the day and at night. The evening trough level was significantly lower than the morning trough level; 185 ng · ml−1 versus 223 ng · ml−1. This, together with a significantly longer t1/2 in the night than the day, suggested circadian variability in the pharmacokinetics of CsA. In a separate retrospective study in 162 renal transplant recipients given CsA by constant intravenous infusion, repeated CsA blood concentration measurements at steady state showed lower concentrations during the day than the night, suggesting higher CsA clearance during daytime. It is concluded that CsA pharmacokinetics in renal transplant recipients, besides the well-known interindividual variability, also displays large intraindividual variability as well as circadian variation. Our findings further emphasize the necessity and difficulty of pharmacological monitoring in the clinical use of CsA in organ transplantation.
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  • 39
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    European journal of clinical pharmacology 44 (1993), S. 301-302 
    ISSN: 1432-1041
    Keywords: Adriamycin ; Haemodialysis ; adriamycinol ; pharmacokinetics ; moment analysis
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  • 40
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    European journal of clinical pharmacology 44 (1993), S. 305-306 
    ISSN: 1432-1041
    Keywords: Atenolol ; bioavailability ; intestinal absorption ; pharmacokinetics
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary We investigated the dose proportionality after the intake of oral atenolol 25, 50, 100 and 150 mg. Standard tablets were taken by 8 healthy volunteers in randomised order of doses. The area under the curve divided by dose did not differ between the doses, indicating that the absorption of this hydrophilic compound, with known incomplete bioavailability, was constant over the range tested.
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  • 41
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    European journal of clinical pharmacology 45 (1993), S. 255-260 
    ISSN: 1432-1041
    Keywords: Ramipril ; Propranolol ; interaction ; pharmacokinetics ; pharmacodynamics
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary We have studied the pharmacodynamic effects of ramipril, propranolol, and their combination, as well as the effect of propranolol on the pharmacokinetics of ramipril in 12 healthy men (age 24 (SD 6) y, weight 72 (7) kg). Propranolol and placebo, ramipril and placebo, or propranolol and ramipril were given orally for four days in a crossover, double-blind fashion. The pharmacokinetics of ramipril and ramiprilat were investigated on day 4. Effects on plasma renin activity, ACE activity, and heart rate and blood pressure both before and after a standardized exercise test were measured on days 1 and 4. On day 4 the combination reduced the mean arterial pressure by 2.8 mmHg compared with propranolol alone and by 3.7 mmHg compared with ramipril alone. Ramipril had no effect on the bradycardia induced by propranolol. Propranolol reduced exercise mean arterial pressure by 9 mmHg (day 4) and heart rate by 7 beats.min−1 (day 4) compared with ramipril; this was not affected by co-administration of ramipril. On day 4 the average plasma renin activity was not significantly higher than after the combination. ACE activity was not affected by propranolol. The pharmacokinetics of ramipril and ramiprilat were not influenced by propranolol. The combination of ramipril and propranolol has additive pharmacodynamic effects that may be useful in the treatment of hypertension.
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  • 42
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    European journal of clinical pharmacology 45 (1993), S. 275-277 
    ISSN: 1432-1041
    Keywords: Fenoterol ; Pregnancy ; pharmacokinetics ; premature labour
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of the β2-adrenergic drug fenoterol, which is used as a tocolytic agent in pregnancy, has been investigated in pregnant (n=9) and nonpregnant (n=5) women during a constant rate intravenous infusion. Clearance and mean residence time were found to be 1990 (1879/2220; Median, Q25/Q75) ml/min and 9.2 (8.0/14.0) min in the pregnant and 2126 (1915/2130) ml/min and 16.6 (16.5/32.1) min in the nonpregnant women, respectively. In addition, fenoterol clearance was estimated in 88 women from a single blood sample collected at steady state during IV therapy and the effect of gestational age on clearance was studied. Clearance displayed large inter-individual variation. There was no apparent correlation between clearance and gestational age. We conclude that there is no need to adjust the dose on pharmacokinetic grounds in the course of pregnancy.
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  • 43
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    European journal of clinical pharmacology 44 (1993), S. 195-197 
    ISSN: 1432-1041
    Keywords: Cefotaxime ; Renal insufficiency ; desacetylcefotaxime ; pharmacokinetics ; children
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary It is generally assumed that the renal clearance of drugs in patients with renal impairment are affected to a similar extent regardless of the type of renal disease (intact nephron hypothesis). We have studied the effect of underlying renal disease on the pharmacokinetics of cefotaxime and desacetylcefotaxime in two groups of children (ages 7 to 16 y) with varying degrees of renal dysfunction. Patients in group 1 (n=5) had intrinsic renal disease and those in group 2 (n=5) had extrinsic renal disease, as identified by the primary renal lesion. After a single intravenous dose of cefotaxime timed blood and urine samples were collected for 24 h; cefotaxime and desacetylcefotaxime were measured by HPLC. There were no significant differences between the groups in age, body surface area, urine output, creatinine clearance, total body clearance, nonrenal clearance, renal clearance, and volume of distribution at steady state of cefotaxime, and renal clearance of desacetylcefotaxime. However, the renal clearance: creatinine clearance (CLR:CLCR) ratios for both cefotaxime [1.34 in group 1 vs. 0.51 in group 2] and desacetylcefotaxime [1.58 in group 1 vs. 0.75 in group 2] were statistically significant between the two groups. Group 1 patients had an average CLR:CLCR ratio greater than 1 for both the parent compound and the metabolite, suggesting that net tubular secretion was still intact, despite a diminished glomerular filtration rate (CLCR=24 ml·min−1·1.73 m−2). In contrast, patients in group 2 (CLCR=49) ml·min−1·1.73 m−2) had an average CLR:CLCR ratio less than 1 for both cefotaxime and desacetylcefotaxime, suggesting that renal tubular transport mechanisms did not remain functional in these patients. Our findings suggest that the effect of renal insufficiency on the renal elimination of cefotaxime and its metabolite desacetylcefotaxime may depend on the cause of renal insufficiency.
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  • 44
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    European journal of clinical pharmacology 44 (1993), S. 253-258 
    ISSN: 1432-1041
    Keywords: Bioelectrical impedance ; Gentamicin ; non-invasive technique ; neonates ; predictive models ; pharmacokinetics ; plasma levels
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The use of bioelectrical impedance (BI) analysis as a non-invasive approach for individualising gentamicin therapy in newborn infants has been investigated in a two phase study. In Phase I, 1/impedance and length2 were identified as statistically significant predictors of the distribution volume of gentamicin (Adj R2=0.78, CV=12.42%), and length2/impedance and post-conceptual age were predictors of total systemic clearance (Adj R2=0.83, CV=14.5%), following the administration of 2.5 mg·kg−1 gentamicin to 17 neonates (gestational age (GA) 27 to 36 weeks). In a prospective validation of these relationships in an independent (Phase II) group of 27 infants (GA 26 to 41 weeks), predicted serum gentamicin concentrations were close to those achieved. Several instances of high prediction errors (predicted minus achieved levels) were observed in infants with known or suspected renal impairment and they caused significant (P〈0.05) perturbation in the bias and accuracy of the models. Daily BI measures over a four to five day period were able to detect individual changes in the fat-free body compartments, which were translated into alterations in gentamicin regimens. This simple, non-invasive and relatively inexpensive bedside technique provides a potentially valuable means to individualise gentamicin therapy without relying on the measurement of serum gentamicin concentration.
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  • 45
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    European journal of clinical pharmacology 44 (1993), S. 357-360 
    ISSN: 1432-1041
    Keywords: Famotidine ; Reflux oesophagitis ; intraoesophageal long-term pH-metry ; pharmacodynamics ; pharmacokinetics
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics, pharmacodynamic effect and clinical efficacy of famotidine were studied in 10 patients with reflux oesophagitis Grades I and II. For the pharmacokinetic studies the patients received 20 mg famotidine i. v. The half-life of famotidine was 3.8 h, the total plasma clearance was 297 ml·min−1, and a steady state volume of distribution of 1.21·kg−1 was found. For pharmacodynamic assessment, intraoesophageal pH-metry was performed without and after acute treatment with famotidine 20 mg i. v. and following 3 weeks of oral famotidine 80 mg b. d. The resultant percentage total acid exposure time (pH〈4 within 24 h) were 23.9%, 19.0% and 19.2% (median), respectively (NS). At the end of 6 weeks of oral therapy, symptomatic and endoscopic improvement had occurred in 9 and 5 patients, respectively. Our study shows that the pharmacokinetics of famotidine in patients with reflux oesophagitis is comparable to that in healthy volunteers and peptic ulcer patients. The clinical response to the treatment appeared comparable to that found after other H2-receptor antagonists.
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  • 46
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    European journal of clinical pharmacology 44 (1993), S. 365-367 
    ISSN: 1432-1041
    Keywords: Ciprofloxacin ; Diazepam ; quinolone ; benzodiazepine ; pharmacokinetics
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effects of pretreatment with a seven day course of ciprofloxacin on pharmacokinetics and pharmacodynamics of an intravenous (5 mg) dose of diazepam were investigated in a group of 12 healthy volunteers in a double-blind placebo-controlled crossover study. Ciprofloxacin pretreatment significantly reduced diazepam CL (without ciprofloxacin: 19.5 ml·h−1kg−1; with ciprofloxacin: 12.3 ml·h−1kg−1). Diazepam t1/2 was also prolonged (without ciprofloxacin: 36.7 h; with ciprofloxacin: 71.1 h), but volume of distribution was unaltered (without ciprofloxacin: 1.1 l·kg−1; with ciprofloxacin: 1.1 l·kg−1). However, no significant changes were detected in psychometric tests of digit symbol substitution, tapping rate and short memory, as well as levels of concentration, vigilance and tension measured by visual analogue scales.
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  • 47
    ISSN: 1432-1041
    Keywords: Temocapril ; Liver dysfunction ; angiotensin converting enzyme inhibitor ; diacid ; pharmacokinetics
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Six subjects with normal liver function (Group 1) and 7 patients with liver dysfunction (Group 2; mean ICGR15 value 30.5 (5.2) %; range 16 to 56) received a single oral dose of 1 mg temocapril, a prodrug-type ACE inhibitor, with preferentially excreted by the biliary route. The plasma temocapril concentrations in Group 2 at 30 min and 1 h postdose were significantly higher than in Group 1, but the difference had disappeared 2 h postdosing. Although the half life of temocapril diacid in Group 2 was significantly longer than in Group 1, there was no significant difference between the two groups in AUC, Cmax or tmax. In Group 2, urinary recovery of temocapril was significantly increased, suggesting a possible delay in the bioactivation of temocapril into the diacid, but recovery of the diacid itself was not abnormal. ACE inhibitory action in Group 2 remained unchanged. Temocapril is regarded as an ACE inhibitor the disposition and efficacy of which are little affected in patients with impaired liver function.
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  • 48
    ISSN: 1432-1041
    Keywords: Isradipine ; Diclofenac ; pharmacokinetics ; platelet aggregation ; drug interaction
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In this open, two-period crossover study in 18 healthy male volunteers, a single oral dose of 50 mg diclofenac was administered alone and on day 7 of multiple oral dosing of 5 mg b.i.d. isradipine to assess a possible pharmacokinetic interaction. The effect of these drugs on ex vivo platelet function was also determined. Serial blood samples were obtained over 12-hour periods on three occasions: after the single diclofenac dose; after the morning dose of isradipine on day 6 and after co-administration of both drugs on day 7 of steady-state isradipine administration. Additional samples were taken at 2 h post dose for determination of ex vivo platelet aggregation. Isradipine plasma concentrations were determined by a gas chromatographic method and diclofenac plasma concentrations by an HPLC method. The pharmacokinetic characteristics of diclofenac were unaltered during co-administration. The maximum plasma concentration of isradipine was increased 19.6% during co-administration from 5.06 to 6.05 ng·ml−1. This is not expected to be of clinical importance. Isradipine's apparent total body clearance and steady-state AUC remained unchanged. Ex vivo induced platelet aggregation was not affected by any of the treatments.
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  • 49
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    European journal of clinical pharmacology 45 (1993), S. 555-558 
    ISSN: 1432-1041
    Keywords: Glucagon ; pharmacokinetics ; i.v. infusion ; intranasal spray ; intramuscular administration ; insulin-dependent diabetes mellitus
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of intranasal, an intravenous infusion, and intramuscular glucagon has been studied in 5 healthy subjects and 11 patients with insulin-dependent diabetes mellitus. After infusion the elimination half-life was significantly longer in diabetics (11.9 vs 6.6 min) and the apparent volume of distribution was twice as high in diabetics (0.19 vs 0.37 l·kg−1). The metabolic clearance rates were the same in the two groups (18.9 and 21.3 ml·min−1·kg−1 in controls and in diabetics) and were about twice those previously reported. After 1 mg intranasally the Cmax of immunoractive glucagon (IRG) was similar in diabetic and in healthy subjects. Administration of a higher dose (2 mg) to diabetic patients produced a higher plasma level, although not proportionately so. The AUC after 1 mg was also similar in controls and in diabetics. The elimination half-life in both groups was similar to the value found after IV infusion; it was significantly shorter in controls (5.5 min) than in diabetics (13.8 min). In both groups, mean Cmax was significantly lower than after IM glucagon, the relative bioavailability of 1 mg intranasally vs IM injection being less than 30%. After IM administration, the Cmax and AUC of IRG in controls and in diabetic patients, were identical. The apparent elimination half-life was also similar in the two groups, and was three- to four-times longer (28.6 and 31.4 min) than after infusion or intranasal administration, possibly because estimation of the t1/2 was affected by slow release of the hormone from the site of injection.
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  • 50
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    European journal of clinical pharmacology 45 (1993), S. 563-569 
    ISSN: 1432-1041
    Keywords: Chlorpromazine ; metabolites ; N-oxide ; sulfoxide ; 7-hydroxy ; conjugates ; pharmacokinetics ; first pass metabolism
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary A study was carried out in 11 healthy young men to investigate the pharmacokinetics of chlorpromazine (CPZ) after a bolus intravenous (IV) dose (10 mg) and three single oral doses (25, 50 and 100 mg), with a washout period of two weeks between doses. Plasma levels of CPZ, CPZ N-oxide (CPZNO), CPZ sulfoxide (CPZSO) and both free and conjugated 7-hydroxy-CPZ (7-HOCPZ) were measured by extraction radioimmunoassays. CPZ exhibited multicompartmental pharmacokinetics in most subjects. There was wide between-subject variability in half life (11.05 h), volume of distribution (1215 l), volume of distribution at steady state (642 l) and mean residence time (8.88 h), whereas systemic clearance was somewhat less variable (76.6 l·h−1). All metabolites were present in measurable concentrations in the plasma of 9 of 11 subjects after IV CPZ, whereas free 7-HOCPZ was not detected in the other 2 individuals. With the exception of CPZNO, the biological half lives of the primary metabolites were longer than the half life of CPZ. After oral administration, the percentage of CPZ reaching the systemic circulation intact (F%) was very low (4–38%) and dose dependant. Moreover, both within-subject and between-subject variances were very high. The maximum plasma concentration (Cmax) and area under the plasma concentration versus time curve extrapolated to infinite time (AUC) showed evidence of nonlinearity, whereas half life did not appear to be dose dependant. These data suggest that the high degree of variability in the pharmacokinetics of CPZ is a result of extensive first pass metabolism rather than variation in half life. The mean AUC for the total conjugates of 7-HOCPZ was about two fold higher than that of the parent drug or any other metabolite. This shows that phase II metabolism plays a very significant role in the disposition of CPZ. As a result, the role of CYP2D6 in the 7-hydroxylation of CPZ cannot be fully assessed without taking phase II metabolism into account.
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  • 51
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    European journal of clinical pharmacology 45 (1993), S. 585-587 
    ISSN: 1432-1041
    Keywords: Flumazenil ; benzodiazepine ; absorption ; disposition ; elderly volunteers ; pharmacokinetics ; aging
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In an open design, randomised, two-way cross-over study, a single 2 mg i.v. dose and a single 30 mg oral dose of flumazenil were each administered to a group of healthy young (n=6) and elderly (n=12) volunteers (male: female 2/1). Plasma samples were collected at intervals and intact drug was assayed. Both the IV and oral doses of flumazenil were very well tolerated by both age groups and no severe or unexpected adverse effects were observed. The main complaints were dizziness and headache, mainly after oral dosing, probably due to the higher Cmax and AUC following this route of administration. After 2 mg i. v. the disposition parameters in the two age groups (elderly/young) were very similar: volume of distribution (Vss): 0.88/0.901·kg−1; total body clearance (ClPL): 0.86/0.99 l·min−1; terminal elimination half-life (t1/2β): 1.02/0.91 h. After the 30 mg oral dose the mean Cmax of 87.6 ng·ml−1 (elderly) and 78.4 ng·ml−1 (young) were generally reached within 0.5 to 1 h. In 26% (elderly) and 23% (young), the absolute bioavailability of flumazenil was very similar. It is concluded that the absorption and disposition paramters of flumazenil were not significantly affected by aging.
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  • 52
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    European journal of clinical pharmacology 44 (1993), S. 27-33 
    ISSN: 1432-1041
    Keywords: Nicorandil ; vasodilator ; tolerance study ; blood pressure ; pharmacokinetics ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary We have studied the effects of intravenous nicorandil, a mixed arterial and venous vasodilator, in 48 healthy volunteers. Nicorandil (20, 28, 39, 54, 74, 103, 144, or 200 μg·kg−1) or placebo were given over 5 min to subjects supine (16 subjects, 2 doses) or sitting (32 subjects, 1 dose) in a single-blind crossover design. Electro-cardiographic intervals, blood pressure, and heart rate were measured before and for 8 h after dosing. Blood and urine safety laboratory studies were also performed before and after dosing. All intravenous infusions of nicorandil and placebo were well tolerated and there were no clinically important safety concerns. The most frequent adverse event after nicorandil was headache (24 events by 19 subjects), although its occurrence was not strictly dose related. One subject experienced transient symptomatic hypotension (144 μg·kg−1). Mean plasma nicorandil concentrations were dose-related and fell with a half-life of 0.7 to 1.2 h. Systemic clearance and volume of distribution tended to decrease as dose increased. Sitting subjects showed marginally lower (〈20%) systemic clearances and larger values of Cmax and AUC. Nicorandil produced dose-related reductions in blood pressure, with consistent statistically significant differences from placebo after the 144 and 200 μg·kg−1 doses. The falls in blood pressure were greater for diastolic pressure and in this supine position. At 200 μg·kg−1, the mean falls in systolic/diastolic pressures (mm Hg) during the first hour were 10.9/14.7 supine and 6.1/9.1 sitting; systolic pressure returned to baseline after 8 h and diastolic pressure after 4 h. Heart rate increased transiently (mean peak increase of 17–24 bpm at the end of the 144 and 200 μg·kg−1 infusions). Blood pressure and heart rate changes over time were statistically significantly correlated with plasma nicorandil concentrations. Individual areas under the blood pressure and heart rate change curves likewise correlated with plasma concentration curve areas.
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  • 53
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    European journal of clinical pharmacology 44 (1993), S. S31 
    ISSN: 1432-1041
    Keywords: Cefmenoxime ; Renal failure ; continuous haemofiltration ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The elimination of cefmenoxime after single and repeated i. v. dosing was studied in 12 patients with severe renal failure and sepsis during continuous haemofiltration. More than 30 % of the drug was found in the filtrate. The sieving coefficient (S) was 0.54. Vss % was unchanged 0.311 · kg−1 in comparison with patients with normal renal function, whereas the mean t/12ß was prolonged to about 16 h, and total clearance was reduced 20.8 ml · min−1 · 1.73 m−2. Once daily administration of 1 g cefmenoxime is suggested as the appropriate dose under such circumstances.
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  • 54
    ISSN: 1432-1041
    Keywords: Oxprenolol ; β-adrenoceptor blockade ; circadian rhythm ; haemodynamics ; pharmacokinetics ; exercise ; healthy volunteers ; kinetic-dynamic model
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary We have studied the effect of dosage time of oxprenolol (Trasicor®) on its pharmacokinetics and pharmacodynamics in six healthy volunteers. The drug effects measured were heart rate and systolic blood pressure during exercise. Oxprenolol was taken orally at 08.00 h, 14.00 h, 20.00 h, and 02.00 h in randomized order, with 1 week between successive doses. There were differences in the pharmacokinetics of oxprenolol for the ratio between the apparent volume of distribution and systemic availability (P=0.04) and for elimination half-life (P=0.006). Both were lowest after administration at 14.00 h (163 (77) l and 1.2 (0.6) h; mean (SD)) and highest after administration at 02.00 h (229 (100) l, and 1.7 (0.6) h). The systolic blood pressure during exercise before oxprenolol did not vary with dosage time, but heart rate during exercise before intake was lowest before dosage time 08.00 h and highest before dosage time 20.00 h (P=0.03). The time-course of heart rate during exercise after oxprenolol was described by a model that incorporated the factors drug concentration and spontaneous diurnal variation. EC50 and Emax did not vary between dosage times. The spontaneous diurnal variation in heart rate during exercise was unaffected by oxprenolol, leading to an apparently greater effect of oxprenolol during the night than during the day.
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  • 55
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    European journal of clinical pharmacology 44 (1993), S. S53 
    ISSN: 1432-1041
    Keywords: Quinapril ; Renal failure ; quinaprilat ; haemodialysis ; ACE inhibitor ; pharmacokinetics ; pharmacodynamics ; peritoneal dialysis ; adverse effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics and pharmacodynamics of the ACE inhibitor quinaprilat have been studied in six chronic haemodialysis (HD) patients and in six patients undergoing continuous ambulatory peritoneal dialysis (CAPD) after a single oral dose of 2.5 mg quinapril. Mean tmax and Cmax values (SEM) for quinaprilat in interdialytic HD patients were 4.0 (0) h and 84 (8.4) ng · ml−1 respectively, and they did not differ significantly from those in CAPD patients (4.7 (0.7) h and 64 (5.7) ng · ml−1). Elimination half lives were 30 (10.1) h (HD) and 34 (7.3) h (CAPD). Cmax, tmax, t/12, and AUC were increased and CL was decreased compared to data reported previously after giving 2.5 mg to healthy subjects. Peritoneal clearance was calculated as 0.1 (0.1) ml · min−1, thus less than 0.5 % of the dose were removed within 24 h by CAPD. ACE activity was suppressed by more than 93 % between 4 and 24 h postdose (P 〈 0.001). It decreased in both groups with increasing plasma quinaprilat levels. Angiotensin II concentration compared to baseline was significantly decreased at 4 hours (−30.4±10 %) and 24 h (−30±9.9 %) (P 〈 0.05,n=11), while active plasma renin concentration was still significantly increased at 48 h postdose (+60.2±14.5 %,P 〈 0.01). Mean arterial pressure 24 h postdose was significantly (P 〈 0.05) decreased in HD (−12 mm Hg) and CAPD patients (− 20 mm Hg). Only two patients reported unwanted effects (fatigue, dizziness, nausea, and weakness). In conclusion, due to its long lasting effect on ACE activity and on blood pressure in terminal renal failure a starting dose of quinapril 2.5 mg o. d. may be used in hypertensive HD and CAPD patients.
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  • 56
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    European journal of clinical pharmacology 44 (1993), S. 361-364 
    ISSN: 1432-1041
    Keywords: Tulobuterol ; β2-adrenoceptor agonist ; aerosol inhalation ; transdermal delivery ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary We have studied the pharmacokinetics of tulobuterol given transdermally or by aerosol inhalation in healthy male volunteers. Tulobuterol was rapidly absorbed after inhalation, with a tmax of 0.8–1.5 h. The Cmax and the AUC increased linearly with dose. Tulobuterol was well absorbed after transdermal administration, with an absorption lag-time of about 4 h. The Cmax and AUC increased linearly with dose and the tmax was about 9–12 h. The mean percentage of drug absorbed during the application of a patch for 24 h was 82–90% after a single dose and 82–85% during repeated dosing. The mean urinary recoveries as unchanged drug after a single inhalation and patch application were 3–4% and 5–6% respectively. Tulobuterol did not accumulate during repeated inhalation or transdermal application. It was well tolerated, except for an increase in heart rate of 10–20 beats · min−1 after five repeated applications of a 4 mg patch.
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  • 57
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    European journal of clinical pharmacology 44 (1993), S. 387-389 
    ISSN: 1432-1041
    Keywords: Flosequinan ; Congestive heart failure ; elderly ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary We have investigated the pharmacokinetics of the direct vasodilator flosequinan in elderly patients with congestive heart failure. Eight patients received a single dose of 50 mg, and 8 patients received once-daily treatment with 25 mg for two weeks. In the single dose study, the tmax of flosequinan was 2.5 h, Cmax was 1.17 μg · ml−1 and t1/2 was 5.63 h. The tmax of the metabolite BTS 53554 was 20.3 h, Cmax was 1.44 μg · ml−1 and t1/2 was 62.0 h. BTS 53554 accumulated gradually in the 14-day repeated dose study and steady-state was reached after approximately 2 weeks. Flosequinan was not found to accumulate. Adverse reactions were not observed in either the single or repeated dose study. It is advisable to consider renal function and body weight when flosequinan is to be administered to elderly patients with congestive heart failure. The initial dose should be 25 mg.
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  • 58
    ISSN: 1432-1041
    Keywords: Metoprolol ; controlled-release formulation ; hydrochlorothiazide ; pharmacokinetics ; pharmacodynamics ; healthy volunteers ; efficacy
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary We have studied a controlled-release formulation containing metoprolol 100 mg and hydrochlorothiazide 12.5 mg. We compared the pharmacokinetics of both substances and the pharmacodynamics of metoprolol with those of a conventional combination tablet. The controlled-release formulation gave less variable plasma metoprolol concentrations, Cmax 138 nmol·l−1 and Cmin 74 nmol·l−1, whereas for the conventional formulation the mean Cmax of metoprolol was 629 nmol·l−1 and the Cmin 20 nmol·l−1. Despite lower relative systemic availability (68%) for metoprolol from the controlled-release formulation and a smaller AUC, metoprolol from the controlled-release formulation produced a greater total effect, calculated as the area under the curve of the effect on exercise heart rate vs. time (303 vs. 259%·h; P〈0.05). Hydrochlorothiazide was rapidly absorbed from both formulations and the plasma concentration profiles were almost superimposable. Controlled-release metoprolol with hydrochlorothiazide combines effective β1-adrenoceptor blockade for 24 h without affecting the pharmacokinetics of hydrochlorothiazide.
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  • 59
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    European journal of clinical pharmacology 38 (1990), S. 343-346 
    ISSN: 1432-1041
    Keywords: indomethacin ; cerebrospinal fluid ; pharmacokinetics ; protein binding ; analgesic activity
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Plasma and cerebrospinal fluid (CSF) concentrations of indomethacin have been determined in 52 patients hospitalized for nerve-root compression pain. Samples of blood and CSF were collected at the same time in each subject, 0.5 to 12 h after a single intramuscular injection of 50 mg indomethacin. Analgesic effect was assessed by the absolute and percentage variation in Huskisson's visual analogue scale between dosing and sampling. According to its high lipid solubility, indomethacin rapidly crossed the blood-brain barrier, being detected in CSF 0.5 h after administration. After attainment of equilibrium within 2 h, the CSF level exceeded the free plasma level. Since the drug was extensively bound to serum albumin (99.7±0.1%), this phenomenon may represent a slight degree of binding of indomethacin in CSF. The analgesic activity was not related to either the plasma or CSF concentration of indomethacin.
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  • 60
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    European journal of clinical pharmacology 38 (1990), S. 523-524 
    ISSN: 1432-1041
    Keywords: tolbutamide ; hydroxytolbutamide ; carboxytolbutamide ; urinary excretion ; age ; pharmacokinetics
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Tolbutamide (1 g/70 kg) was administered as a single intravenous dose to 31 healthy, non-smoking, drug-free males between 23 and 87 years old and the total amounts of hydroxy and carboxytolbutamide excreted in 24 h were measured. There was a significant decrease in the urinary recovery of both metabolites with age. The reason for these findings is not known at the present time and may be associated with the decrease in creatinine clearance observed in these subjects or other changes in the pharmacokinetics of tolbutamide which are currently being investigated.
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  • 61
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    European journal of clinical pharmacology 38 (1990), S. 499-503 
    ISSN: 1432-1041
    Keywords: 2-mercaptopropionylglycine ; body clearance ; half-life ; pharmacokinetics ; protein binding
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of 2-mercaptopropionylglycine (2-MPG) was studied in ten healthy volunteers after a single i. v. injection of 250 mg (1532 μmol). The total and non-protein-bound concentrations versus time curves were best described by a three-exponential function with terminal half-lives of 55 and 59 h respectively. Body clearance based upon the total concentration was estimated to be 105 and 231 ml/min based on the non-protein-bound 2-MPG. The corresponding values for Vss were 99 l and Vss,n 173 l, and for Vγ485 l and Vγ,n 1121 l respectively. 75% of the dose was excreted in the urine, mainly during the first 6 h after injection. The proportion of non-protein-bound 2-MPG diminished exponentially during the first 15 h and then levelled off at about 30%. There was a nonlinear increase in the non-protein-bound fraction of 2-MPG as the total plasma concentration of the drug increased.
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  • 62
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    European journal of clinical pharmacology 38 (1990), S. 526-527 
    ISSN: 1432-1041
    Keywords: phenytoin ; posture ; pharmacokinetics ; plasma levels
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  • 63
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    European journal of clinical pharmacology 39 (1990), S. 487-490 
    ISSN: 1432-1041
    Keywords: sulphadimethoxine ; plasma concentration ; skin blister fluid concentration ; pharmacokinetics
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The time-dependent concentration curves of sulphadimethoxine in plasma and cantharidin-induced skin blister fluid have been evatuated following a single oral dose of 1 g. In contrast to other drugs, sulphadimethoxine exhibited two-stage penetration into the blister fluid, the second peak concentration being higher than the first. The maximum plasma concentration of 94.1 mg·l−1 was observed after 4 h, and in skin blister fluid the first peak of 25.6 mg·l−1 was found after 7 h, and the second of 58.0 mg·l−1 occurred after 30 h. The penetration of sulphadimethoxine into skin blister fluid, defined as the ratio of the AUC there to that in plasma was 0.748. The results suggest that sulphadimethoxine penetrates into skin blister fluid to a great extent from plasma and achieves concentrations exceeding the MIC for susceptible pathogens, but it requires a relatively long time to do so.
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  • 64
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    European journal of clinical pharmacology 38 (1990), S. 209-211 
    ISSN: 1432-1041
    Keywords: Isradipine ; hypertension ; pharmacokinetics ; pharmacodynamics ; clinical trial
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In conjunction with a multicentre clinical trial of the calcium antagonist isradipine in hypertension, pharmacokinetic and pharmacodynamic studies were conducted in 9 subjects. An initial dose of 5 mg (capsule formulation) of isradipine was given orally. The mean Cmax, tmax and AUC(0–8) were 6.0 ng · ml−1, 1.5 h and 15.1 h · ng · ml−1 respectively. Seven subjects repeated the study at steady state after 10 week's dose titration with isradipine. Cmax, tmax and AUC(0–8) were 3.7 ng · ml−1, 1.2 h and 12.2 h · ng · ml−1 respectively indicating that the drug does not accumulate over time. Control of blood pressure paralleled plasma isradipine concentrations which suggested that the drug should be given at least twice daily. Pharmacokinetic studies performed in conjunction with clinical trials can provide valuable information about the patterns of drug response.
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  • 65
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    European journal of clinical pharmacology 39 (1990), S. 583-586 
    ISSN: 1432-1041
    Keywords: ranitidine ; piroxicam ; interaction ; pharmacokinetics ; healthy volunteers
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effects of piroxicam (40 mg) on the pharmacokinetics of ranitidine (150 mg) and of ranitidine (150 mg bid) on the pharmacokinetics of piroxicam (20 mg) were assessed in two 2-way crossover studies in two groups of 18 healthy male subjects. In the first study there were no statistically significant differences between the pharmacokinetic variables for ranitidine in the presence or absence of piroxicam. The mean maximum plasma concentration (Cmax) was 467 ng·ml−1 for ranitidine alone and 466 ng·ml−1 in the presence of piroxicam; mean area under the plasma concentration vs time curve (AUC) was 2460 h·ng ml−1 and 2551 h·ng ml−1 respectively; and the mean terminal half-life (t 1/2) was 3.6 h and 3.8 h respectively. In the second study there were no statistically significant differences between the pharmacokinetic variables for piroxicam in the presence or absence of ranitidine. The mean Cmax was 2.1 μ·ml−1 in the presence of placebo and 2.0 μg·ml−1 in the presence of ranitidine respectively; mean AUC was 133 h·μg ml−1 and 137 h·μg ml−1 respectively, and the mean t 1/2 was 53.6 h and 54.5 h respectively.
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  • 66
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    European journal of clinical pharmacology 39 (1990), S. 613-614 
    ISSN: 1432-1041
    Keywords: Thioridazine ; debrisoquine polymorphism ; pharmacokinetics ; adverse effects
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  • 67
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    European journal of clinical pharmacology 38 (1990), S. 255-258 
    ISSN: 1432-1041
    Keywords: theophylline ; mequitazine ; drug interaction ; pharmacokinetics ; asthma
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effect of an oral anti-allergic drug, mequitazine, on the pharmacokinetics of theophylline has been investigated in seven asthmatic patients. They received chronic theophylline therapy (a sustained-release theophylline tablet 200–400 mg b.d. at 12 h intervals) and coadministered mequitazine 6 mg for 3 weeks. Plasma theophylline concentration-time curves and the urinary excretion of theophylline and its major metabolites before and after coadministration of mequitazine were compared. No significant change in the pharmacokinetic parameters of theophylline or in the urinary recovery of unchanged drug and its metabolites was observed. Thus, mequitazine did not influence the pharmacokinetics of theophylline and it should be safe for coadministration to asthmatic patients on chronic theophylline therapy.
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  • 68
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    European journal of clinical pharmacology 38 (1990), S. 259-263 
    ISSN: 1432-1041
    Keywords: tacrine ; amyotrophic lateral sclerosis ; postoperative sedation ; pharmacokinetics
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of 9-amino-1,2,3,4-tetrahydroacridine; tacrine, THA, was studied after intravenous administration and following the first and last oral doses of a seven week clinical trial involving 8 patients with amyotrophic lateral sclerosis, ALS. Two surgical patients given intravenous THA for reversal of postoperative sedation were also included. Plasma concentration of THA and in some cases the metabolite, 1-hydroxy-THA, were assayed using a selective and sensitive method with high performance liquid chromatography. After an intravenous dose of 30 mg THA, the plasma concentrations were fitted to a two-compartment model. Plasma clearance showed a threefold interindividual variation with a mean of 2.42 l·h−1. Volume of distribution, Vα varied 100–680 l with a mean of 349 l. The plasma half-lives of distribution and elimination were 1.8 and 98.2 min, respectively. Oral bioavailability showed large interindividual differences and ranged 6–36% in the four subjects studied. After seven weeks treatment with oral THA, plasma concentrations immediately prior to medication were below 10 ng/ml in three patients and above 100 ng/ml in two patients. At the same occasion the plasma metabolite concentrations considerably exceeded those of THA. THA medication was associated with side effects in the majority of the patients.
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  • 69
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    European journal of clinical pharmacology 38 (1990), S. 269-273 
    ISSN: 1432-1041
    Keywords: flecainide ; quinine ; pharmacokinetics ; metabolism inhibition ; drug interaction ; renal transport
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of flecainide and its two sequential metabolites, both free and conjugated, its pharmacodynamics, and the influence of simultaneously administered quinine, have been studied in 10 healthy subjects. The study comprised two, 48-h open phases at an interval of 1 week. Flecainide acetate 150 mg was given as a 30-min i.v. infusion and quinine sulphate orally 500 mg×3 over 24 h. Quinine administration did not change the apparent volume of distribution or the renal clearance of flecainide, but it significantly reduced its systemic clearance (9.2 vs 7.6 ml · kg−1 · min−1), thus increasing the elimination half-life (9.6 vs 11.5 h). The amount of flecainide transformed to its first, meta-O-dealkylated metabolite (MODF) fell with no change in the renal excretion of the latter, either in its free or conjugated forms. This finding, in association with a fall in amount of the second, meta-O-dealkylated lactam metabolite (MODLF) recovered in its conjugated forms in the urine, suggests that quinine inhibits both the first and the second steps of the sequential metabolism of flecainide. When the subjects received quinine in addition to flecainide, the PR interval in the ECG was slightly more prolonged than with flecainide alone. Due to the study design, an effect of quinine per se and the consequence of increased serum flecainide levels could not be distinguished.
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  • 70
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    Keywords: celiprolol ; renal failure ; pharmacokinetics ; enantioselective kinetics
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of the ß1-selective adrenergic antagonist (R,S)-celiprolol has been studied after oral administration of 200 mg celiprolol-HCl to 8 healthy volunteers and 8 patients with various degrees of impaired renal function. No significant difference was found between the two enantiomers in the control group or in the patients. In healthy volunteers an average of 9.8% of the dose of R-(+)-celiprolol and 9.5% of S-(-)-celiprolol was recovered unchanged in the urine. Renal impairment reduced the urinary excretion of both enantiomers to the same extent according to the severity of the uraemia, producing higher AUCs. Nevertheless, the terminal half-lives of the R- and S-enantiomers were not significantly different between the groups. Dosage reduction in patients with renal impairment does not seem to be necessary.
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  • 71
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    European journal of clinical pharmacology 38 (1990), S. S53 
    ISSN: 1432-1041
    Keywords: nitrates ; pharmacokinetics ; pharmacodynamics ; nitrate tolerance ; isosorbide-5-mononitrate
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Healthy male volunteers received three different dose regimens of a controlled-release form of isosorbide-5-mononitrate (IS-5-MN; 60 mg per tablet). Dose regimen I consisted of a single daily dose of 60 mg given for 5 days. Dose regimen 11 was started with a dose of 60 mg, followed by 30 mg 12 h later and thereafter every 8 h. The last dose, on the 5th day was again 60 mg. In dose regimen III60 mg followed by 30 mg 6 h later were administered every day for 5 days. The peripheral arterial and venous effects of IS-5-MN during the first and last dosing interval were followed by changes in the finger pulse curve, standing systolic blood pressure, heart rate, and venous distensibility. Plasma concentrations of IS-5-MN were measured frequently following the first and the last dose. Following dose regimen I all hemodynamic effects produced by the first dose were maintained during the study. The maximal plasma concentrations were about 400 ng/ml and the trough value, lower than 100 ng/ml. Following dose regimen II the hemodynamic effects of IS-5-MN and sublingual glyceroltrinitrate were completely abolished on the 5th day. Trough plasma concentrations were approximately 300 ng/ml during the entire study period. Following dose regimen III pronounced hemodynamic effects were seen on the 1st day. However, a significant attenuation of the hemodynamic effects was measured on the 5th day, when trough plasma concentrations were between 100 and 230 ng/ml. There was a significant negative correlation between the magnitude of hemodynamic effect remaining on the 5th day (measured by the area under the finger pulse curve) and the trough plasma concentration. Thus, the maintenance of minimum plasma concentrations of IS-5MN of 300 ng/ml or higher produces a rapid development of hemodynamic nitrate tolerance, whereas no tolerance was found when the plasma concentrations were allowed to decline below 100 ng/ml before the next dose was given. A significant attenuation of hemodynamic effects was found when minimum plasma concentrations were between 100 and 230 ng/ml. The degree of attenuation in this concentration range increased with increasing trough plasma concentrations.
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  • 72
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    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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  • 73
    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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  • 74
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    European journal of clinical pharmacology 17 (1980), S. 111-116 
    ISSN: 1432-1041
    Keywords: zimelidine ; norzimelidine ; antidepressants ; pharmacokinetics ; bioavailability
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    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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  • 75
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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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  • 76
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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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    European journal of clinical pharmacology 18 (1980), S. 517-520 
    ISSN: 1432-1041
    Keywords: desmethyldiazepam ; oxazepam ; cimetidine ; hepatic elimination ; pharmacokinetics ; interaction
    Source: Springer Online Journal Archives 1860-2000
    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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    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
    Source: Springer Online Journal Archives 1860-2000
    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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    European journal of clinical pharmacology 18 (1980), S. 269-273 
    ISSN: 1432-1041
    Keywords: paracetamol ; thyrotoxicosis ; hypothyroidism ; drug disposition ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    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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  • 80
    ISSN: 1432-1041
    Keywords: alminoprofene ; antalgic ; pharmacokinetics ; single dose ; multiple doses
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    Topics: Chemistry and Pharmacology , Medicine
    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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  • 81
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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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  • 82
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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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  • 83
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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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  • 84
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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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  • 85
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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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  • 86
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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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  • 87
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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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  • 88
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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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  • 89
    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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  • 90
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    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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  • 91
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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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  • 92
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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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  • 93
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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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  • 94
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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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  • 95
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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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  • 96
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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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  • 97
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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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  • 98
    ISSN: 1432-1041
    Keywords: carteolol ; pharmacokinetics ; beta-adrenoreceptor blocking drug ; absolute bioavailability ; plasma levels ; urinary excretion ; renal handling
    Source: Springer Online Journal Archives 1860-2000
    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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  • 99
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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
    Source: Springer Online Journal Archives 1860-2000
    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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  • 100
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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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