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  • 1975-1979  (13,786)
  • Polymer and Materials Science  (13,298)
  • Rat
  • pharmacokinetics
  • 1
    Electronic Resource
    Electronic Resource
    Springer
    Psychopharmacology 66 (1979), S. 63-66 
    ISSN: 1432-2072
    Keywords: Tryptophan ; Uptake ; Kinetics ; Serotonin ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The kinetics of synaptosomal tryptophan accumulation has been determined in five regions of the rat brain. For tryptophan concentrations ranging from 2.5–20 μM, we found an active uptake in all the structures studied, i.e.: Corpus striatum, midbrain, brainstem, hypothalamus and cerebral cortex + hippocampus. The Vm of tryptophan uptake was highest in the cortex, followed in descending order by corpus striatum, hypothalamus, midbrain and brainstem, while the Km was highest in the cortex, then in descending order corpus striatum, brainstem, midbrain and hypothalamus. In spite of the possible nonspecific high affinity tryptophan uptake into serotoninergic neurons, we found a correlation between the Vm of tryptophan uptake and the different results in the literature concerning uptake and release of serotonin. These observations might indicate a correlation between the Vm of tryptophan uptake and the functional activity of serotonergic neurons.
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  • 2
    Electronic Resource
    Electronic Resource
    Springer
    Psychopharmacology 66 (1979), S. 67-71 
    ISSN: 1432-2072
    Keywords: Ethanol ; Conflict ; Avoidance ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The effects of ethanol on avoidance-avoidance conflict behavior were examined, utilizing a 3-×-3 factorial design in which rats were trained and tested after drinking sugar-water solutions containing 0,3, or 6% ethanol. Avoidance tendencies were established by initially training rats to escape from electric shock fy running in one direction in a white alley, and in the opposite direction in a black alley. In subsequent shock free conflict tests, the rats were placed into an alley with one black wall and one white wall, an environment in which incompatible tendencies to avoid both ends of the alley were aroused. During training, ethanol decreased the speeds with which rats escaped shock. In the subsequent avoidance-avoidance conflict tests, rats that previously received shock escape training after drinking ethanol ran more slowly, and exhibited lower total movement and oscillation range scores than did animals trained after drinking plain sugar-water. Administration of ethanol just prior to the conflict tests resulted in dose-related increases in running speeds, total movement scores, and oscillation ranges. These results suggest that moderate doses of ethanol increased responding by differentially weakening conflicting avoidance tendencies.
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  • 3
    Electronic Resource
    Electronic Resource
    Springer
    Psychopharmacology 61 (1979), S. 191-195 
    ISSN: 1432-2072
    Keywords: Emotional reactivity ; Open field ; Heart rate ; Atropine ; Propranolol ; Autonomic nervous system ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract It has been shown in male rats of two albino strains, Wistar and Sprague-Dawley, that differences in emotional reactivity were related to physiological differences (Bernet and Denimal, 1978). Particularly the resting heart rate was slower in the more emotionally reactive rats. It has been suggested that emotional reactivity is linked with a certain neurovegetative balance. This possibility was investigated in twelve rats of each strain by means of differential blockade of the autonomic nervous system by atropine and propranolol. The heart rate response of the emotionally reactive strain to propranolol was statistically smaller than that of the non reactive strain. On the other hand, the heart rate increase resulting from atropine treatment was more elevated in the same rats. The calculated sympathetic and parasympathetic tones (as % of intrinsic heart rate) were 8% and 30% respectively in the reactive rats. However, both of the tones were 14% in the non reactive rats. In conclusion, the high defecating rats in the open-field exhibit a lower sympathetic tone linked with a higher parasympathetic tone.
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  • 4
    ISSN: 1432-2072
    Keywords: Rat ; Alcohol ; Withdrawal ; Audiogenic seizure ; Cholinergic enzymes ; Nucleus caudatus ; Hippocampus
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The enzymes of the cholinergic system have been investigated in discrete brain areas in alcohol-dependent rats, which were still intoxicated or were undergoing withdrawal. The ethanol intoxication resulted in a slight, but significant increase in choline acetyltransferase (CAT) activity in the caudate nucleus both 1 and 7 h after the last dose of ethanol. We also found a significant decrease in CAT activity in the temporal limbic cortex while rats were highly intoxicated. All other brain regions investigated, e.g., cerebellum, pons-medulla, frontoparietal cortex, hypothalamus and septum showed unchanged CAT activity. Rats were also analysed immediately following the onset of a withdrawal-induced audiogenic convulsive seizure where, in addition to the striatum, depressed CAT activity was observed in the hippocampus. In all the analysed situations acetylcholinesterase activity remained unchanged. These results show that ethanol intoxication leads to a perturbation in the synthetic capacity of acetylcholine in certain defined brain structures and that this may have some correlation to the observed behavioural impairments.
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  • 5
    ISSN: 1432-2072
    Keywords: Met-enkephalin ; Brain ; Prostaglandins ; Rat ; Temperature
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract An enhanced prostaglandinlike activity is shown in homogenates of brain from rats treated intracerebroventricularly with 100 μg of metenkephalin. The increase is significantly reduced by naloxone pretreatment. A relationship is proposed between generation of prostaglandins in the brain following met-enkephalin administration and hyperthermic effect of the opiatelike factor in the rat. Normalization of prostaglandinlike activity following chronic administration of met-enkephalin in the rat may also account for the development of tolerance to its thermic effect.
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  • 6
    Electronic Resource
    Electronic Resource
    Springer
    Psychopharmacology 65 (1979), S. 171-177 
    ISSN: 1432-2072
    Keywords: Morphine ; Rat ; Self-administration ; Physical dependence ; Addiction ; Reinforcement ; Behavior
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Groups of naive rats were offered morphine sulfate for self-administration in doses of 0.0032–10 mg/kg for 6 days. On day 7 saline was substituted for morphine. Loss of weight was taken as physiological evidence of dependence. Rats that did not lose weight formed a single population whose mean injection rate did not differe from control rats receiving only saline injections. Injection rates for rats losing weight were log-normally distributed, and the mean of the logarithms of the injection rates was linearly related to the logarithm of the dose. Mean daily injection rates averaged 12 for controls, 23 at 10 mg/kg, and 411 at 0.01 mg/kg. A transient increase in morphine intake after an injection of nalorphine was taken as behavioral evidence of dependence. Nalorphine increased morphine intake when rats were self-injecting 0.32 and 1.0 mg/kg of morphine, but not 0.032 or 0.1 mg/kg. The reinforcing property of morphine may occur without behavioral evidence of dependence.
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  • 7
    ISSN: 1432-2013
    Keywords: Rat ; Renal hypertension ; Unclipping ; Redipping ; Reactivity of blood pressure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Moderate or severe hypertension was induced in rats by application of a clip 0.25 or 0.20 mm internal diameter) to the left renal artery leaving the contralateral kidney intact. Removal of the clip 6, 13 or 24 days after the induction of the hypertension was followed by a rapid decrease in blood pressure. A near normotensive level was reached after 2–6 h. Reapplication of the clip to the unclipped renal artery after 1 day caused an enhanced blood pressure response. The preoperative hypertensive levels were reached within 2 h. This enhanced response was related to the level of blood pressure before the removal of the clip. Lengthening the interval between removal and reapplication of the clip gradually reduced the enhanced response of blood pressure, which had disappeared 8 days after the removal of the clip. Reapplication of the clip to the contralateral renal artery was not followed by an enhanced response in rats with previous moderate or severe hypertension.
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  • 8
    Electronic Resource
    Electronic Resource
    Springer
    Pflügers Archiv 380 (1979), S. 189-195 
    ISSN: 1432-2013
    Keywords: Heart rate ; Rat ; Sex difference ; Body weight
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract In unanesthetized Sprague Dawleys, SPF, of both sexes, housed indl 12:12 (110 lux), at a temperature of 18–23°C and a hygrometry of 60–75%, the measurements of heart frequencies during most part of their life point out a continuous decrease with age and an always higher (40–20 c. min−1) heart rate in females than in males. Significant correlations between rate and body weight can account for these heart which corresponds to the growth period, a linear relationship was established between Log heart rate (y;c. min−1) and Log body weight (x; gram); for males: Logy=−0.122 Logx+Log 938 and for females: Logy=−0.166 Logx+Log 1217. After the age of 600 days, which corresponds to senescence, decreases in heart rate as well as in body weight were observed in both sexes.
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  • 9
    ISSN: 1432-2013
    Keywords: Rat ; Micropuncture ; Microperfusion ; Loop of Henle ; Stop-flow pressure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The behavior of the feedback mechanism, that causes glomerular capillary pressure and filtration rate to decrease when tubule fluid flow rate through the loop of Henle of the same nephron is increased, was examined in rats before and during isotonic extracellular fluid volume expansion. The loop of Henle was perfused from the late proximal tubule at either 10 or 40 nl/min while proximal fluid was collected to measure single nephron filtration rate (SNGFR), while proximal stop-flow pressure (PSF) was measured, or while fluid was collected from the early distal tubule to assess reabsorption of fluid and electrolytes by the loop of Henle. During control periods increasing loop perfusion caused SNGFR to decrease 37%, PSF to decrease 19%, and absorption of fluid, sodium and chloride by the loop of Henle to increase. After 1 h of infusion of isotonic NaCl solution the same change in loop flow causes a 19% decrease in SNGFR and an 8% decrease in PSF. Fluid absorption by the loop of Henle did not increase with increased loop perfusion. Increases in Na and Cl absorption were similar to the increases in control periods. The smaller decreases in SNGFR and PSF indicate that acute volume expansion decreases the sensitivity of the feedback response. The mechanism of this decrease in gain could involve interference with local generation or action of angiotensin, or a change in the composition or pressure of interstitial fluid tending to dilate the pre-glomerular resistance vessels.
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  • 10
    ISSN: 1432-2013
    Keywords: Foetal kidney ; Ammoniagenesis ; Gluconeogenesis ; Acidosis ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Ammoniagenesis and gluconeogenesis have been studied in foetal rat kidneys during the five last days of gestation by measuring in vitro NH3 and glucose productions from glutamine and by assaying activities of soluble phosphoenolpyruvate carboxykinase (PEPCK) and glucose 6-phosphatase (G6Pase). These studies were carried out in normal (mean blood pH: 7.30) and acidotic (pH: 7.12) foetuses. In normal foetuses, NH3 production by kidney cortex slices remains constant throughout the studied period of development, at a level 10-fold lower than the maternal one. On day 20 of gestation, a low glucose production (20-fold lower than the maternal one) appears for the first time. This may be related to an increase of PEPCK and G6Pase activities which occurs between day 19 and 20. In 20 days old foetuses, NH4Cl induced acidosis stimulates NH3 production but has no effect on PEPCK activity and glucose production. A response of gluconeogenesis to acidosis is observed one day later (day 21).
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  • 11
    Electronic Resource
    Electronic Resource
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 306 (1979), S. 105-112 
    ISSN: 1432-1912
    Keywords: Intestinal absorption ; Vascular perfusion ; Drugs ; Urea ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary 1. The absorption of antipyrine, salicylic acid, and urea was measured in vascularly perfused segments of rat intestine. The results were compared with absorption in segments of intestine which were prepared in an identical manner, but not perfused with blood. 2. Compared to in situ results obtained earlier, the absorption of antipyrine and salicylic acid increased 3-fold; the absorption of urea, 2-fold. The absorption of the drugs in the unperfused segments was reduced 60%; however, the absorption of urea remained unchanged. Blood flow apparently limits drug absorption, but not urea absorption. 3. A certain amount of the drugs permeated into the serosal bath in the blood-perfused segments of intestine: approximately 20% of the antipyrine and urea, but only 2% of the salicylic acid. This accounts for the difference between the disappearance rate and the venous appearance rate. 4. Histological examination revealed no morphological alterations in the blood-perfused segments when compared with control specimens. The water and glucose absorption rates were within the range obtained in earlier in vivo investigations. 5. The glucose consumption of the tissue was increased in the non-vascularly perfused intestine; apparently the oxygen supply was insufficient. The histological alterations may be the result of insufficient oxygen supply or water storage within the tissue.
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  • 12
    ISSN: 1432-1335
    Keywords: 2-Chloroethylnitrosoureas ; Leukemia L 5222 ; Rat ; 2-Chlorethylnitrosoharnstoffe ; Leukämie L 5222 ; Ratte
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Zusammenfassung Die therapeutische Aktivität der vier neusynthetisierten Nitrosoharnstoffe 1-(2-Chlorethyl)-1-nitroso(3-methylencarboxamido)-harnstoff (Acetamido-CNU), 1-(2-Chlorethyl)-1-nitroso-3-(4-morpholino)-harnstoff (Morpholino-CNU), 1-(2-Chlorethyl)-1-nitroso-3-(1-piperidino)-harnstoff (Piperidino-CNU) und 2-[3-(2-Chlorethyl)-3-nitrosoureido]-ethylmethansulfonat (Ethylmethansulfonato-CNU) wurde an der präterminalen Rattenleukämie L 5222 mit der Wirkung von BCNU, CCNU, MeCCNU, Chlorozotocin und Hydroxyethyl-CNU verglichen. MeCCNU war den anderen Substanzen im Hinblick auf den breiten Dosisbereich, in dem eine mediane Überlebenszeit von 〉90 Tagen bewirkt wurde, überlegen. Chlorozotocin dagegen bewirkte als einzige Substanz in dieser Versuchsanordnung keine Heilungen. Von den neu vorgestellten Substanzen waren die wasserlöslichen Verbindungen Acetamido-CNU und Morpholino-CNU im Hinblick auf die Breite des Dosisbereiches, in dem eine mediane Überlebenszeit von 〉90 Tagen erzielt wurde, annähernd dem CCNU vergleichbar. Piperidino-CNU und Ethylmethansulfonato-CNU bewirkten auch Heilungen; jedoch wurde nur mit einer Dosierung von Piperidino-CNU eine mediane Überlebenszeit von 〉90 Tagen erreicht.
    Notes: Summary The newly synthesized nitrosoureas 1-(2-chloroethyl)-1-nitroso-3-(methylenecarboxamido)-urea (Acetamido-CNU), 1-(2-chloroethyl)-1-nitroso-3-(4-morpholino)-urea (Morpholino-CNU), 1-(2-chloroethyl)-1-nitroso-3-(1-piperidino)-urea (Piperidino-CNU), and 2-[3-(2-chloroethyl)-3-nitrosoureido]-ethylmethanesulfonate (Ethylmethanesulfonato-CNU) were compared in their chemotherapeutic activity against preterminal rat leukemia L 5222 with BCNU, CCNU, MeCCNU, Chlorozotocin, and Hydroxyethyl-CNU. With respect to the dose range effecting a median survival time of more than 90 days, MeCCNU was superior to the other substances. Chlorozotocin, on the other hand, was the only substance which achieved no cures in this experimental arrangement. From the four newly introduced substances the water-soluble substances Acetamido-CNU and Morpholino-CNU were approximately comparable to CCNU with regard to the dose range effecting a median survival time of 〉90 days. Piperidino-CNU and Ethylmethanesulfonato-CNU also effected cures; however, only Piperidino-CNU in one dosage effected a median survival time of 〉90 days.
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  • 13
    Electronic Resource
    Electronic Resource
    Springer
    Calcified tissue international 27 (1979), S. 161-164 
    ISSN: 1432-0827
    Keywords: Osteoporosis ; Ovary ; Rat ; Vitamin D
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine , Physics
    Notes: Summary Fifty adult female rats were used to study the effect of 1-alpha-hydroxyvitamin D3 (1α-OH-D3)on bone after oophorectomy. The experimental period was 6 months. At the end of the experiment the femurs and the tibias were investigated for bone mass and composition. Significant signs of osteopenia occurred as a result of oophorectomy. The treatment with 1α-OH-D3 induced only minor changes in blood chemistry but increased bone mass significantly. The findings support the view that 1α-OH-D3 may be a valuable tool in the treatment of osteoporosis resulting from ovarian insufficiency.
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  • 14
    Electronic Resource
    Electronic Resource
    Springer
    Archives of dermatological research 264 (1979), S. 225-241 
    ISSN: 1432-069X
    Keywords: Biorheology ; Mechanical parameters ; Step phenomenon ; Low extension ; Skin ; Rat ; Biorheologie ; mechanische Parameter ; Stufenphänomen ; geringe Dehnung ; Haut ; Ratte
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Zusammenfassung Bei eingehenden Untersuchungen der Biomechanik der Haut von Ratten zeigte sich ein eigenartiges Verhalten, das sowohl bei konstanter Abzugsgeschwindigkeit (Kraftdehnungsexperimente) als auch bei konstanter Belastung (Kriechexperimente) auftrat. Bei konstanter Dehnung nahm die Spannung nicht kontinuierlich zu, sondern fiel 2 oder 3 mal partiell ab, bevor der steile Teil der Kraftdehnungskurve einsetzte. Dieses Verhalten, das als Stufenphänomen bezeichnet wird, wird bei geringen bis mittleren Dehnungen und relativ geringen Belastungen ausgelöst. In den meisten Fällen wurden 2, manchmal auch 3 Stufen beobachtet. Die Möglichkeit von Artefakten wurde ausgeschlossen. Das Phänomen trat hauptsächlich an Proben der Rückenhaut von Ratten, die quer zur Körperrichtung ausgestanzt waren, auf. Es kann dadurch erklärt werden, daß im Fasernetzwerk der Haut bestimmte Bindungen reißen und damit eine momentane zusätzliche Verlängerung eintritt, bis andere Bindungselemente die Zugkräfte aufnehmen. Da frühere Untersuchungen einen ausgeprägten Einfluß auf Alterung und Reifung sowie von desmotropen Substanzen auf die mechanischen Eigenschaften beim A briß, wie z. B. Reißfestigkeit, Elastizitätsmodul und Dehnung bis zum Abriß, gezeigt haben, lag es nahe, auch das Stufenphänomen unter diesen Bedingungen zu untersuchen. Bei den Kraftdehnungsexperimenten wurden die meisten Stufen in einem Alter von 2 bis 4 Monaten gefunden. Der den Stufen zuzurechnende, aufsummierte Spannungsverlust und der aufsummierte Energieverlust waren am höchsten in einem Alter von 4 Monaten. Wenn jedoch diese Werte als Prozentsatz der Werte beim Abriß berechnet wurden, so wurden die höchsten Zahlen bei jungen Tieren gefunden. Die auf die Stufen zurückzuführende Dehnungszunahme zeigte ebenfalls ein Maximum zur Zeit der Reifung, also nach 4 Monaten. Ähnliche Befunde wurden in den Kriechexperimenten erhoben, wenn mit einer mittleren Belastung von 200 g gearbeitet wurde. Nach Behandlung mit Prednisolonazetat wurden mehr und nach Behandlung mit d-Penicillamin weniger Stufen beobachtet. In den Kraftdehnungsexperimenten waren der aufsummierte Spannungsverlust und der aufsummierte Energieverlust bei Prednisolon-behandelten Ratten mehr als doppelt so hoch als bei den Kontrollen und etwa nur die Hälfte nach d-Penicillamin-Behandlung. Wenn diese Werte als Prozentsatz der Werte beim Abriß berechnet wurden, so verschwanden die Unterschiede, da die Veränderungen von Reißfestigkeit und Gesamtenergieaufnahme gleichgerichtet waren. Jedoch die auf die Stufen zurückzuführende Dehnungszunahme, die durch d-Penicillamin signifikant erniedrigt und durch Prednisolonacetat statistisch nicht signifikant erhöht war, zeigte diese Veränderungen auch, wenn sie als Prozentsatz der Dehnung beim Abriß berechnet wurde. Unter allen hier geprüften Bedingungen beeinflußte das Stufenphänomen hauptsächlich die Dehnungsparameter. Die hier berichteten Befunde bestätigten frühere Beobachtungen, daß die mechanischen Eigenschaften bei geringer Belastung oder geringer und mittlerer Dehnung zumindest teilweise ein verschiedenes Verhalten zeigen, sowohl unter dem Einfluß der Reifung und der Alterung als auch nach Behandlung mit desmotropen Substanzen, als es für die mechanischen Eigenschaften beim Abriß der Proben gefunden wurde.
    Notes: Summary Comprehensive analysis of the mechanical properties of rat skin revealed the “step phenomenon”. This particular observation was made after constant strain rate (analysis of stress strain curves) as well as after constant load (creep experiments). Relative low extensions or low loads were necessary to provoke the steps. In most cases two, sometimes three steps were observed. The step phenomenon was found mainly in skin strips punched out perpendicularly to the body axis. Probably some bonds in the fibrous network are broken giving way to additional elongation whereafter stronger links take over the stress. Since earlier studies demonstrated a pronounced influence of age and of desmotropic drugs on mechanical properties at ultimate load, e.g., tensile strength, ultimate modulus of elasticity, and ultimate strain, also the step phenomenon was studied under these conditions. In stress-strain experiments most of the steps were found at the ages of 2 and 4 months. Total stress loss and total work loss due to the steps were the highest at the age of 4 months. If, however, these values were calculated as percentage of ultimate values, the highest figures were found in young animals. Elongation gain due to the steps also showed a maximum at time of maturation, e.g., 4 months. Similar findings were achieved in creep experiments at medium load (200 g). After treatment with prednisolone acetate more steps and after treatment with d-penicillamine fewer steps were observed. In stress-strain experiments total stress loss and total work loss due to steps were more than twice as high than controls after prednisolone treatment and only one half after d-penicillamine. If calculated as percentage of ultimate stress or percentage of work input, these changes disappeared because of similar changes at ultimate load. However, elongation gain due to steps, which was not significantly influenced by prednisolone acetate but significantly decreased by d-penicillamine, showed the same changes when calculated as percentage of ultimate strain. Under all conditions the step phenomenon mainly influenced the extension parameters. The data presented here confirm earlier observations that mechanical properties at low loads or low and medium extensions show at least to some extent a different pattern under the influence of maturation and age and after treatment with desmotropic drugs compared to the mechanical parameters at ultimate load.
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  • 15
    Electronic Resource
    Electronic Resource
    Springer
    Anatomy and embryology 156 (1979), S. 177-187 
    ISSN: 1432-0568
    Keywords: Yolk sac ; Prenatal catecholamines ; Extraneuronal catecholamine localization ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Catecholamines were found histochemically in the visceral yolk sac of the rat from embryonic day (ED) 10, i.e. before the amines become detectable in peripheral or central neurons of the fetus. Formaldehydeinduced fluorescence was confined to the apical part of the yolk sac epithelial cells. The specificity of histofluorescence has been confirmed by borohydride reduction, microspectrofluorimetry revealing an emission peak at 480 nm and administration of reserpine. The catecholamines present were identified by mass fragmentography using N,O-trifluoroacetyl derivatives. At ED 13 both dopamine and norepinephrine were present, while only dopamine was detected at ED 181/2. Maternal circulation or the epithelial cells themselves appear as possible sources of these catecholamines. The occurrence of amines in the yolk sac epithelium may reflect an intracellular role of these compounds, a barrier function of the epithelium or a step in a transport to the fetus where the amines might assume regulatory functions.
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  • 16
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    Anatomy and embryology 157 (1979), S. 311-328 
    ISSN: 1432-0568
    Keywords: Visual cortex ; Development ; Pyramidal neurons ; Non-pyramidal neurons ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The postnatal development of neuronal perikarya in layers II–VI of the visual cortex of perfusion-fixed albino rats, 12 h to 180 days old, has been studied by electron microscopy. Particular attention was paid to cells in photographic montages of 75μm wide strips extending through the full depth of the occipital cortex, cut from 100 μm vibratome sections of the brain. At birth, and during the first few postnatal days, most of the neurons present in the cortex are small, tightly packed ‘indifferent’ cells with scanty cytoplasm containing mitochondria and chiefly free ribosomes; a few presumptive pyramidal cells with a developing apical dendrite and more voluminous cytoplasm can be recognized in deep cortex. Non-pyramidal cells can be identified on postnatal day 6, when although scarce and with immature cytoplasmic features, they already display a more electron opaque chromatin pattern than developing pyramidal cells and receive axo-somatic contacts of Gray's type I. During the second postnatal week there are conspicuous increases in the maturity of the cells, which acquire a rich complement of cytoplasmic organelles: in general cells situated in the deep cortical plate are larger and better differentiated than those in the superficial plate, and non-pyramidal cells are less well differentiated than the associated pyramidal cells. By the end of the second week, differences in cytoplasmic maturity between superficial and deep, and between pyramidal and non-pyramidal cells are less evident. Maturation proceeds during the third postnatal week; both types of cells acquire an adult complement of axo-somatic synapses and their mature nuclear and cytoplasmic features, and by day 24 are indistinguishable from their adult counterparts. In keeping with previous Golgi studies of this same cortex, the non-pyramidal cells did not acquire mature ultrastructural features significantly later than the pyramidal cells. A possible correlate of particularly active synaptogenesis and plasticity in the population of nonpyramidal, cells during the third postnatal week (immediately after eyeopening), was that at this time these cells contained very prominent accumulations of granular reticulum, ribosomes and Golgi apparatus, and appeared hypertrophic.
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  • 17
    Electronic Resource
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    Anatomy and embryology 155 (1979), S. 1-14 
    ISSN: 1432-0568
    Keywords: Visual cortex ; Non-pyramidal neurons ; Development ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary We have studied the maturation of non-pyramidal cells in layers II–VI of the visual cortex of albino rats from birth to maturity, using Golgi-Cox and rapid Golgi preparations. At birth, non-pyramidall cells are sparse, immature and concentrated in the deep part of the cortical plate: their number increases towards the end of the first week but they remain sparse and immature in the upper part of the cortical plate. During the second postnatal week, the number, size and extent of dendritic and axonal branching of these cells undergo considerable increases and the cells become conspicuous in layer IV and apparent in the supragranular layers: this “growth spurt’ occurs just after (and may be related to) the arrival and establishment in the cortex during the second half of the first postnatal week, of extrinsic afferents. During the third postnatal week, most of the cells complete their maturation. At the end of this week, the number of spinous cells is greater and the spine density of some cells is higher than in the adult, falling to adult values during the fourth postnatal week. It is noteworthy that the non-pyramidal cells appear to reach maturity at about the same time in all the layers studied, and at the same time as the pyramidal cells with which they are associated. These observations are not in accord with the prevalent view that non-pyramidal cells complete their differentiation much later than pyramidal cells.
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  • 18
    Electronic Resource
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    Acta neuropathologica 46 (1979), S. 203-208 
    ISSN: 1432-0533
    Keywords: Choroid plexus ; Rat ; Chloroquine ; Chlorphentermine ; Lipidosis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Several cationic amphiphilic drugs, each of which is known to induce generalized lipidosis in rats, were compared with respect to their cytological effects on rat choroid plexus epithelium. Chloroquine induced large cytoplasmic vacuoles, whereas the other drugs (quinacrine, 4,4′-diethylaminoethoxyhexestrol, chlorphentermine, iprindole, 1-chloro-amitriptyline, clomipramine) caused formation of lamellated or crystalloid inclusions as usually seen in drug-induced lipidosis. The ultrastructure of the chloroquine-induced vacuoles suggested storage of water-soluble materials (polar lipids and/or non-lipid materials) in addition to non-water-soluble polar lipids.
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  • 19
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    Acta neuropathologica 47 (1979), S. 123-130 
    ISSN: 1432-0533
    Keywords: Rat ; Protein deprivation ; Neocortex ; Vessels ; Morphometry
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The postnatal vascular growth in the neocortical area 18 of normal and pre- and postnatally protein-deprived rats was examined. For control rats the specific length, the specific surface and the volume fraction of vessels increased rapidly between 7 and 20 days of age. Thereafter, only a minor increase was seen. In protein-deprived rats there was no increase in the specific length of vessels between 7 and 10 days of age and this variable was still reduced at 30 days of age compared to controls. This reduction was due to a decrease in the specific length of thin vessels (Ø〈8.25 μ) whereas the specific length of wider vessels was not affected by the protein deprivation. There were no significant differences in the specific surface or volume fraction of vessels between control and protein-deprived rats. These findings indicate an adaptive increase in luminal diameter of vessels in the protein deprived rats during postnatal development. At 90 days of age no significant differences between vascular variables of control and protein-deprived rats were seen.
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  • 20
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    Acta neuropathologica 47 (1979), S. 139-143 
    ISSN: 1432-0533
    Keywords: Perineurium ; Permeability ; Peripheral nerve ; Rat ; Ultrastructure ; Autoradiography ; Albumin ; Peroxidase ; Protein deprivation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The permeability properties of the perineurium in sciatic nerves of 12-week-old rats were studied. The penetration of125I-labeled albumin and horseradish peroxidase into the perineurium was investigated electronmicroscopically 10, 30, and 120 min after the local extraneural application of the tracers. The autoradiographic study included age-matched protein-deprived rats. It was concluded that the perineurium acted as a diffusion barrier but also permitted a slow passage of the macromolecules into the endoneurium. The result indicates that this penetration to some extent is due to vesicular transport across the perineurial cells. The significance of these barrier and transport properties of the perineurium is discussed. No obvious differences in perineurial permeability between normal and protein-deprived rats were obtained.
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  • 21
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    European journal of clinical pharmacology 15 (1979), S. 105-108 
    ISSN: 1432-1041
    Keywords: muzolimine ; cardiac failure ; pharmacokinetics ; high ceiling diuretics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of a new “high ceiling” diuretic, muzolimine (Bay g 2821), were investigated after a single oral dose of 40 mg in 7 patients with cardiac failure (Stages I–IV, New York Heart Association classification), and in 2 healthy subjects. Plasma concentrations peaked 1–3 h after administration and declined according to a two-compartment model. The α-phase (distribution phase) lasted until 12–16 h after administration and the mean t1/2α was 3.6 h (range 2.3–4.7) in patients, and 2.6 h (range 2.3–2.9) in healthy subjects. The mean t1/2β was 13.5 h (range 7.4–22.4) in the patients and 14.0 h (range 12.4–14.6) in healthy subjects. T1/2β was not correlated with the degree of heart failure or with the area beneath the plasma concentration curve, which varied three-fold. The renal clearance of muzolimine was in the range 2.7–15.3 ml · min−1 in 5 subjects in whom it was investigated. The pharmacokinetics of muzolimine appear not to be significantly altered by cardiac failure. The prolonged half-lives of the drug are probably responsible for the longer duration of diuretic action reported for muzolimine than for furosemide and bumetamide.
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  • 22
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    European journal of clinical pharmacology 15 (1979), S. 115-120 
    ISSN: 1432-1041
    Keywords: digoxin ; right heart failure ; absorption ; absolute bioavailability ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The absorption of digoxin has been investigated in 8 patients before and after successful treatment of severe right heart failure.3H-digoxin 0.1 mg as a solution, and un-labelled digoxin 0.25 mg as a tablet, were given to fasted patients. Blood samples were taken at various time intervals up to 120 hours and urine was collected over the same period. The concentrations of labelled digoxin in plasma and urine were measured in a liquid scintillation counter, unlabelled digoxin was estimated by radioimmunoassay, and various pharmacokinetic parameters were calculated. There was no significant difference in the plasma concentration curves in severe right heart failure and after its successful treatment, nor did any of the calculated pharmacokinetic parameters change significantly. Therefore, inhibition of the absorption of digoxin appears unlikely. In an additional study to estimate absolute bioavailability two different groups of patients in severe right heart failure were given3H-digoxin 0.1 mg or unlabelled digoxin 0.25 mg i. v. and the pharmacokinetic parameters were compared with those from the previous study. The bioavailability of the3H-digoxin solution and of the digoxin tablet were in the same range as values previously published for healthy volunteers, and patients both with and without cardiac failure.
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  • 23
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    European journal of clinical pharmacology 15 (1979), S. 187-192 
    ISSN: 1432-1041
    Keywords: quinidine ; plasma protein binding ; pharmacokinetics ; man
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The disposition and plasma protein binding of quinidine after intravenous administration were studied in 13 healthy subjects. Plasma protein binding, expressed as the fraction of quinidine unbound ranged from 0.134–0.303 (mean 0.221). Elimination rate constant (β) varied from 0.071 to 0.146 h−1 (mean 0.113), and apparent volume of distribution (Vβ) varied from 1.39–3.20 l · kg−1β (mean 2.27). Total body clearance was 2.32–6.49 ml min−1 · kg−1. There was a positive linear correlation between the plasma fraction of unbound quinidine and both Vβ (r=0.885, p〈0.01) and total body clearance (r=0.668, p〈0.05). No significant correlation existed between the fraction of unbound quinidine in plasma and the elimination rate constant. The results show that both the apparent volume of distribution and total body clearance of quinidine are proportional to the unbound fraction in plasma. This implies that the total plasma concentration of quinidine at steady state will change with alterations in plasma binding, whilst the concentration of unbound compund and its elimination rate will remain unaffected.
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  • 24
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    European journal of clinical pharmacology 15 (1979), S. 175-180 
    ISSN: 1432-1041
    Keywords: clorazepate ; nordiazepam ; pregnancy ; pharmacokinetics ; intramuscular injection
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary A single dose of clorazepate 20 mg was injected i.m. in 7 pregnant and 7 non-pregnant women. Blood samples were collected for one week, and urine was collected for 24 h after the dose. The concentrations of clorazepate and its metabolite nordiazepam were determined by electron capture gas liquid chromatography. There was no difference between the two groups on physical examinations. Clorazepate was rapidly absorbed and the peak concentration was reached within 2h. Mean pharmacokinetic parameters for clorazepate were absorption half life 0.77h in pregnant women and 0.56h in non-pregnant women; elimination half life 1.3h in pregnant women and 2.0h in non-pregnant women; volume of distribution: 0.43 l · kg−1 in the pregnant women and 0.33 l · kg−1 in non-pregnant women. Nordiazepam reached its peak concentration within 12h after dosing; its mean half life of elimination was 180h in pregnant women and 60h in non-pregnant women. Within 24h, 1.3% of the clorazepate was recovered in urine from pregnant women and 7% in urine from the non-pregnant women.
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  • 25
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    European journal of clinical pharmacology 16 (1979), S. 203-209 
    ISSN: 1432-1041
    Keywords: dantrolene sodium ; spasticity ; twitch tension ; dose response ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Dantrolen sodium is a muscle relaxant, which is used in the treatment of spasticity. Although it is given chronically, little is known about its pharmacokinetic behaviour. The relationship between the effect of a single oral dose of dantrolene sodium and its plasma concentration in healthy volunteers was studied by measuring the effect on the twitch tension, and in spastic patients on the decrease in muscle hypertonia. On the twitch tension dantrolene gave a depression of 49.1±9.4% (±SD) within 1.15 and 3.45 h after ingestion of 100 mg. The mean maximal plasma concentration was 1.24±0.32 µg/ml (±SD). The effect and the plasma concentration were correlated. No relationship between the plasma concentration of dantrolene sodium and its effect could be established in patients, although definite activity in 6 out of 7 patients was observed after a single oral dose of 100 mg, and plasma concentration of dantrolene sodium greater than 0.3 µg/ml were consistently associated with better results than placebo treatment in 6 out of 7 patients.
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  • 26
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    European journal of clinical pharmacology 16 (1979), S. 263-270 
    ISSN: 1432-1041
    Keywords: diazepam ; alcoholic beverages ; plasma level ; pharmacokinetics ; co-ordination skills ; red wine ; white wine ; whisky
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Twenty paid healthy students ingested diazepam 10 mg 30 min after the administration of ethanol 0.8 g/kg. The alcoholic beverage used was varied in randomized double-blind experiments, which were repeated at one-month intervals. Psychomotor performance, plasma diazepam, and alcohol concentration in breath were measured 30, 60, 90 min and 2, 3, 4, 6 and 24 h after the ingestion of diazepam. Beer and white wine elevated the plasma level of diazepam and the effect lasted for up to 2 h. Whisky elevated the diazepam level for 90 min. Red wine did not affect it significantly. The alcohol-diazepam combination impaired tracking skills and oculomotor co-ordination and enhanced nystagmus, more than diazepam alone. Red wine produced a breath alcohol concentration higher than after white wine. More nystagmus was recorded after red wine and diazepam, although white wine led to a higher plasma diazepam concentration. It appears that simultaneous ingestion of alcohol and diazepam accelerates the absorption of diazepam. This pharmacokinetic alteration may not contribute much to the combined psychomotor effects of diazepam and alcohol, which were mainly due to pharmacodynamic interaction at receptor level.
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  • 27
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    European journal of clinical pharmacology 16 (1979), S. 271-277 
    ISSN: 1432-1041
    Keywords: lithium ; litarex ; single dose ; multiple dose ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary An analysis of the single and multiple dose pharmacokinetics of lithium in 7 healthy volunteers is presented. A solution of lithium chloride was administered in single dose experiments and the same solution and a sustained release preparation were employed in multiple dose experiments, which were carried out at steady state. A fixed dose of 24 mmol was used in the single dose experiments and in the subsequent multiple dose experiments in the same subjects the same dose was administered once daily for a week. Distinct two-compartment characteristics were found, with a mean disposition rate constant (β) of 0.035 h−1±0.010 SD, corresponding to a mean biological half-life of about 19.8 h. The mean half-time of the distributory α-phase was about 1.15 h. The absorption of lithium from an orally administered solution took place with a half-time of about 0.15 h in the single dose experiments. The apparent volume of distribution of the central compartment (Vc) was 0.307 1 kg−1±0.046 SD, less than half that of Vde at equilibrium. Vdβ (Vdarea) was 0.8291 kg−1±0.184 SD and mean total body clearance was 27.6 ml kg−1 h−1±4.7 SD.
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  • 28
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    European journal of clinical pharmacology 16 (1979), S. 255-262 
    ISSN: 1432-1041
    Keywords: spironolactone ; canrenone ; fluorimetry ; high performance liquid chromatography ; linear kinetics ; saturation kinetics ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In Study I 20 normal volunteers received a single oral dose of spironolactone 100 mg. In Study II a further 20 normal volunteers were given first spironolactone 100 mg b.i.d. and subsequently spironolactone 100 mg once a day for a further 4 days. In Study III 5 normal subjects were given a single dose of spironolactone 500 mg. The concentration of canrenone in serum was determined both by fluorimetry and HPLC for 0–48 h in Study I, 120–168 h in Study II and 0–36 h in Study III. The total AUCs after the single 100 mg dose did not differ from the AUCs within the dosing interval during steady state. The half-lives of the terminal log-linear phases were almost identical (14.99±0.80 h and 15.69±0,80 h) when determined by fluorimetry, and were sligthly, but significantly (p〈0.01), longer when determined by HPLC — 20.14±1.62 and 18.71±1.04. The mean ratio of the specific AUC determined by HPLC and the fluorimetrically determined AUC was 0.3 after the single 100 mg dose. It did not differ from the corresponding value during steady state (0.34). In contrast, the ratio after the single 500 mg dose was approximately 50% higher. Fluorimetrically determined AUCs after 100 and 500 mg doses did not show dose-proportionality in contrast to the HPLC-determined AUCs. It was concluded that Canrenone contributes much less to the conventional fluorimetric determination than was previously assumed. It may not provide more than 1/10 and 1/4 of the antimineralocorticoid activity of spironolactone after single dose and multiple doses, respectively. Whereas linear kinetics apply after single and multiple 100 mg doses of spironolactone, after 500 mg saturation kinetics must be assumed with respect to metabolism. Thus, in bioavailability studies high doses of spironolactone should be avoided. For such studies the fluorimetric assay seems to be the appropriate bioanalytical method in spite of its lower specificity.
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  • 29
    ISSN: 1432-1041
    Keywords: prenalterol ; metoprolol ; haemodynamics ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The haemodynamic effects of the selectiveβ 1-adrenoceptor agonist prenalterol were studied in healthy subjects before and after therapeutic doses of the selectiveβ 1-adrenoceptor blocker metoprolol. Plasma levels of the drugs were also determined in order to calculate certain pharmacokinetic variables. Intravenous infusion of prenalterol 0.13, 0.25 and 0.50 mg induced a dose-dependent decrease in total electromechanical systole (QA2) and pre-ejection period (PEP). The effect on left ventricular ejection time (LVET) was not significant. Increases in systolic blood pressure and heart rate were dose-dependent. Diastolic blood pressure did not change significantly. When metoprolol had been administered in a cumulative dose of 150 mg (mean maximal plasma level, 284 nmol/1) prenalterol had to be administered in doses that were twelve times higher than before theβ-blocker in order to induce the same haemodynamic effects. Prenalterol was rapidly distributed with an average half life of 8 min. This indicates that distribution equilibrium will be achieved within 30 min after intravenous administration. The overall elimination rate in the post-distributive phase corresponded to an average half life of 2.0 h.
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  • 30
    ISSN: 1432-1041
    Keywords: triamterene ; pharmacokinetics ; diuretic effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The plasma and urinary levels of triamterene and two metabolites were measured using a specific method of analysis. Urinary excretion was completed after 48 h, which permitted a rough estimate of its half-life as longer than two hours. The areas under the curve were 672.5±160.3 and 1.311.3±399.1 µg/ml × h after the triameterene 150 mg and 300 mg p.o., respectively and correspondingly 4.2±1.4% and 3.7±0.6% of the dose were excreted as unchanged drug. The principal metabolite of triamterene found was the sulfate conjugate. The area under the curve of this metabolite amounted to 6.672±2.120 and 11.941±5.005 µg/ml × h after the of 150 mg and 300 mg triamterene doses, respectively. The urinary excretion of the metabolite varied between 25.0±4.0% and 17.5±3.5% of the dose after either dose. In healthy subjects an effect on sodium excretion was observed after a dose of 150 mg, whereas the potassium-retaining effect was observed only after the dose of 300 mg.
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  • 31
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    European journal of clinical pharmacology 16 (1979), S. 31-38 
    ISSN: 1432-1041
    Keywords: bezafibrate ; hyperlipoproteinemia ; bioavailability ; pharmacokinetics ; GC-MS
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The disposition kinetics of bezafibrate, a newly developed drug of great lipid-lowering potency, were investigated in normal male subjects. Five male volunteers received14C-labelled bezafibrate orally in solution, and a further 10 were given the same dose (300 mg) of un-labelled drug as tablets. The concentration of bezafibrate in serum and urine from the latter was determined by GC, and in the former total radioactivity in serum, urine and feces was followed for 48 h, and urinary excretion products were analysed by TLC and GC-MS. Rapid absorption from the gastrointestinal tract led to peak serum levels 30 min and 2 h after administration of solution and tablets, respectively. Since approximately 95% of the administered14C-bezafibrate was excreted in urine within 48 h, and almost all the remainder was detected in feces, absorption can be regarded as complete after administration in solution. The relative optimal bioavailability from the tablets was also complete, since in both cases approximately 50% of the administered dose was detected as unchanged bezafibrate in urine within 24 h by GC in the tablet study, and by TLC in the solution study. Of the decomposition products, more than 20% of the dose was present as glucuronides and the remainder consisted of several more polar compounds, one of which was identified as a hydroxyderivative of bezafibrate. Since the apparent halflife of bezafibrate in serum was 2.1 h, this new drug possesses favourable pharmacokinetic features: rapid and complete absorption, even from tablets, combined with a conveniently short half-life, and clearance which is half renal (56 ml/min) and half metabolic (43 ml/min), giving a total clearance of 99 ml/min.
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  • 32
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    European journal of clinical pharmacology 16 (1979), S. 45-48 
    ISSN: 1432-1041
    Keywords: quinidine ; slow release formulation ; pharmacokinetics ; bioavailability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The bioavailability of quinidine in two sustained release preparations A and B has been compared in three females and three males with i.v. administration of quinidine. The initial rate of oral absorption did not differ between the two drug preparations; the peak concentration was observed after 4 h both for A and B, but was significantly higher after B. A slower decrease in plasma concentration was observed after preparation A than B. Absolute bioavailability did not differ significantly between A (median value 78.4%) and B (median 87.1%). Drug absorption in vivo was in good agreement with the results of in vitro dissolution tests on both preparations. The slower decrease in plasma concentration found for the new sustained release form of quinidine should be of clinical advantage.
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  • 33
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    European journal of clinical pharmacology 16 (1979), S. 49-52 
    ISSN: 1432-1041
    Keywords: cephacetrile ; haemodialysis ; pharmacokinetics ; renal failure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of cephacetrile were studied after its administration as a single i.v. bolus injection of 15 mg/kg body weight to 11 patients with terminal renal inpairment undergoing haemodialysis for 6 h. A two-compartment kinetic model was used to describe the biphasic decrease in plasma concentration. The quantities of antibiotic in the central and peripheral compartments, and the amounts eliminated, were calculated for different times. During haemodialysis sessions, the average pharmacokinetic parameters of cephacetrile determined at the dialyser input were: α=5.03 h−1,β=0.458 h−1, K12=2.337 h−1, K21=1.996 h−1 K13=1.154 h−1, Vc=5.508 l, Vp=6.448 l, Vdss=11.956 l. As a function of the pharmacokinetic parameters of cephacetrile, a regimen of multiple doses was established for patients with terminal renal impairment, which will guarantee safe and effective concentrations of the antibiotic.
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  • 34
    ISSN: 1432-1041
    Keywords: methadone ; mass fragmentography ; pulse labeling ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary A technique is presented for study of steady state kinetics of methadone using pulse labeling with deuterated methadone (d3) and mass fragmentography to measure both unlabeled and labeled methadone in blood. Seven subjects maintained on methadone for at least 10 months were admitted to a closed metabolic ward. The daily dose of unlabeled methadone (d0) was substituted by one dose of methadone-d3 and plasma levels of methadone-d0 and methadone-d3 were followed for 48 h using a precise (SD±5%) and sensitive (30 pmol/ml) mass fragmentographic technique. Plasma half-lives (t1/2) for both methadone-d0 and metadone-d3 were calculated from samples obtained 8–24 h following the dose of methadone-d3. The t1/2 of oral methadone-d3 was shorter (22±2 h) than that of methadone-d0 (52±20 h). The same pattern was observed after intravenous administration. The results indicate multiple pools of methadone in the body.
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  • 35
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    European journal of clinical pharmacology 16 (1979), S. 101-105 
    ISSN: 1432-1041
    Keywords: dihydroquinidine ; congestive heart failure ; intravenous administration ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of dihydroquinidine were studied in 8 patients with congestive heart failure following a 22 min intravenous infusion of a quinidine preparation that contained 5.9% dihydroquinidine as an impurity. Using a thin layer chromatography-fluorometric assay procedure for dihydroquinidine, the post-infusion plasma dihydroquinidine concentrations declined biexponentially. The half-life of the fast and slow dispositional processes was 4.42±1.81 min and 6.52±2.40 h, respectively. The central compartment volume for dihydroquinidine in these patients was 0.44±0.11 l/kg with an overall apparent volume of distribution of 1.14±0.38 l/kg. The computed values of total body plasma clearance of dihydroquinidine ranged from 1.29 to 2.69 ml/min/kg with a mean value of 1.94±0.60 ml/min/kg. In these patients, approximately 16% of the administered dihydroquinidine dose was excreted intact into the urine in 48 h. The estimated value of renal clearance was 0.314±0.129 ml/min/kg. When compared to control cardiac patients, the data showed that the apparent volume of distribution for dihydroquinidine is smaller in patients with congestive heart failure and as a result of this diminished volume, the clearance rate of dihydroquinidine was slower. The net effect of these differences was the production of higher plasma concentrations of dihydroquinidine in the heart failure group.
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  • 36
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    European journal of clinical pharmacology 16 (1979), S. 119-124 
    ISSN: 1432-1041
    Keywords: cefoxitin ; renal impairment ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of cefoxitin have been determined after a single i.v. injection of 15 mg/kg body weight in 10 patients with normal renal function and 20 patients with varying degrees of renal impairment. The kinetics of the antibiotic followed an open two-compartment model. In patients with normal renal function the following pharmacokinetic parameters were found: $$\begin{gathered} \begin{array}{*{20}c} {\alpha = 8.66 h^{ - 1} } & {\beta = 1.21 h^{ - 1} } & {K_{12} = 3.47 h^{ - 1} } \\ \end{array} \hfill \\ \begin{array}{*{20}c} {K_{21} = 3.17 h^{ - 1} } & {K_{13} = 3.15 h^{ - 1} } & {V_c = 4.24 l.} \\ \end{array} \hfill \\ \begin{array}{*{20}c} {V_p = 4.87 l.} & { Vd_{ss} = 9.11 l.} \\ \end{array} \hfill \\ \end{gathered}$$ In the patients with renal impairment there was a significant decrease in $$\mathop \alpha \limits_, \mathop \beta \limits_, $$ K12, K21 and K13, and an increase in the apparent volume of distribution. The degree of plasma protein binding in patients with normal renal function was 73.6% and this was diminished in patients with renal impairment. A linear relationship between K13 of cefoxitin and creatinine clearance was demonstrated. The dosage regimen for patients with renal impairment should be adjusted by modifying the dosage interval whilst maintaining the amount administered.
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  • 37
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    European journal of clinical pharmacology 16 (1979), S. 195-202 
    ISSN: 1432-1041
    Keywords: metformin ; biguanides ; pharmacokinetics ; absorption
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The kinetics of14C-metformin have been studied in five healthy subjects after oral and intravenous administration. The intravenous dose was distributed to a small central compartment of 9.9±1.61 ( $$\bar X$$ ±SE), from which its elimination could be described using three-compartment open model. The elimination half-life from plasma was 1.7±0.1 h. Urinary excretion data revealed a quantitatively minor terminal elimination phase with a half-life of 8.9±0.7 h. After the intravenous dose, metformin was completely excreted unchanged in urine with a renal clearance of 454±47 ml/min. Metformin was not bound to plasma proteins. The concentration of metformin in saliva was considerably lower than in plasma and declined more slowly. The bioavailability of metformin tablets averaged 50–60%. The rate of absorption was slower than that of elimination, which resulted in a plasma concentration profile of “flip-flop” type for oral metformin.
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  • 38
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    European journal of clinical pharmacology 16 (1979), S. 279-285 
    ISSN: 1432-1041
    Keywords: salicylate ; synovitis ; osteoarthritis ; arthritis ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Samples of blood and joint fluid from 30 patients who had taken buffered acetylsalicylic acid were examined for concentrations of total salicylates (TSA), acetylsalicylate (ASA) and salicylate (SA). The data were arranged in groups according to diagnosis of the joint disease. Analysis of the data did not show significant difference in the kinetics of TSA into blood. In groups the time to first appearance of 0.3 mg/l averaged 6.3 min for TSA; these values averaged 7.7 min for ASA and 10.9 min for SA. Close to maximum concentrations in blood averaged 18.9 mg/l for TSA, 3.3 mg/l for ASA, and 23.3 mg/l for SA. The time for first appearance of 0.3 mg/l of total salicylates in joint fluid ranged from 10 to 34 min with an average of 18.1 min; the values of ASA averaged 19.4 min and those of SA 21.9 min. The maximum concentration in joint fluid averaged 15.7 mg/l for TSA, 2.5 mg/l for ASA, and 14.5 mg/l for SA. Transport of salicylates from blood to joint fluid showed a pattern consistent with the type of joint disease. Support was found for the hypothesis that diffusion was the major factor in the movement of salicylates from blood to joint fluid.
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  • 39
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    European journal of clinical pharmacology 16 (1979), S. 287-293 
    ISSN: 1432-1041
    Keywords: linear system theory ; perfusion model ; cardiac output ; pulmonary extraction ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Assessment of pharmacokinetics in terms of circulatory drug transport is proposed using the methods of linear system theory. In this model-independent approach drug distribution and disposition are characterized by the total extraction ratio, the mean residence time in the body and the volume of distribution at steady state. In analyzing concentration(c)-time(t) data, the procedure requires calculation only of the areas under the c(t)-and c(t)×t-curves to estimate kinetic parameters, and for prediction of the steady state concentration following continuous infusion or multiple doses. Pulmonary clearance of drugs is included in the theory.
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  • 40
    ISSN: 1432-1041
    Keywords: chlorthalidone ; pharmacokinetics ; oral and i.v. doses ; bioavailability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Seven normal human volunteers each received a constant-rate infusion of chlorthalidone for 2 h, and the same (commonly 50 mg) single oral dose on separate occasions. The concentration of unchanged chlorthalidone was analyzed over a 100 to 220 h period in plasma, red blood cells, urine and faeces after both dosage forms. A three compartment model was required to describe the intravenous plasma concentrations in five of the subjects. A two compartment model sufficed to account for the decay of the oral plasma concentrations in all seven subjects. The mean plasma t1/2 after i.v. dosing was 36.5 h (±10.5 SD), and the mean plasma t1/2 after oral doses was 44.1 h (±9.6 SD). The mean red blood cell concentration t1/2 after i.v. doses was 46.4 h (±9.9 SD), and the mean red blood cell t1/2 after the oral doses was 52.7 h (±9.0 SD). The shorter i.v. half-live was not equally manifest in all subjects, being mainly apparent in three of them. In all cases the urinary excretion rate plots were parallel to the plasma concentration curves. As the faster decay after i.v. administration was not accompanied by increased renal clearance, the difference must have been due to non-renal mechanism. The mean total of 65.4 (±8.6 SD) % of the intravenous dose was excreted in urine over infinite time, whereas the mean total excretion after the oral dose was 43.8 (±8.5 SD) %. Faecal excretion ranged from 1.3–8.5% of dose in the i.v. study to 17.5–31.2% of dose in the oral study. The sum of the amounts present in urine plus faeces pointed strongly to an important metabolic route of elimination of chlorthalidone. Bioavailability estimates (F) from three sets of data were — a mean F of 0.61 from plasma concentrations, 0.67 from urinary excretion measurements and 0.72 from the erythrocyte concentrations. Simulations with a non-linear model indicated lesser validity of the estimate from erythrocyte concentrations. It was concluded that the average of plasma and urine data, F=0.64, yielded the best estimate of the oral availability of chlorthalidone 50 mg in man.
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  • 41
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    European journal of clinical pharmacology 15 (1979), S. 121-125 
    ISSN: 1432-1041
    Keywords: guanethidine ; chronic therapy ; urinary excretion ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The plasma level and urinary excretion rate of guanethidine have been measured in 30 patients during oral maintenance therapy, and in 5 patients following discontinuation of therapy. A significant correlation was found between the daily average urinary excretion and the maintenance dose, although wide interindividual variation was noted among patients maintained on the same dose. A statistically significant correlation was also observed between the area under the plasma level curve during the dose interval and the oral maintenance dose. After discontinuation of chronic therapy, the half-life of 1.5 days of the initial phase of elimination was essentially in agreement with the half-life of almost 2 days determined in acute studies. In addition, a second phase of elimination with a half-life of 4 to 8 days was observed.
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  • 42
    ISSN: 1432-1041
    Keywords: clorazepate ; nordiazepam ; pregnancy ; placental transfer ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Clorazepate 20mg was given i. m. to 49 mothers during the first stage of labour. The elimination of the drug was studied in 27 newborns produced by these mothers. The same dose was given to 13 women who underwent amniocentesis and to 7 women who were breast-feeding. “Total nordiazepam”, i.e. the sum of clorazepate and its metabolite nordiazepam, was determined by gas-liquid chromatography in maternal blood, umbilical cord blood (both arterial and venous), amniotic fluid and in milk. Clorazepate was found to cross the placental barrier slowly, but nordiazepam was transferred more rapidly. Nordiazepam was found in the milk and in the blood of neonates after breast-feeding had started.
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  • 43
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    European journal of clinical pharmacology 15 (1979), S. 269-274 
    ISSN: 1432-1041
    Keywords: phenytoin ; food-intake ; bioavailability ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The influence of food intake on the absorption of phenytoin was examined in eight healthy volunteers, by study of single-dose kinetics following ingestion of phenytoin 300 mg either with a standardized breakfast or on an empty stomach. Blood samples were collected at regular intervals from 0 to 48 h, and serum concentrations of unmetabolized phenytoin were determined by gas chromatography. Serum concentrations of the major metabolite of phenytoin, 4-hydroxyphenytoin, were measured by mass fragmentography. Concurrent intake of food and phenytoin appeared to accelerate absorption of the drug from the formulation used, and the peak concentrations were significantly higher (mean increase 40%) in the postprandial than in the preprandial state. As reflected by the AUC (area under the curve), the amount of drug absorbed was increased during postprandial conditions, although the difference only reached borderline significance. It is suggested that phenytoin should always be taken in a defined relation to meals.
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  • 44
    ISSN: 1432-1041
    Keywords: indobufen ; platelet aggregation ; single dose ; bioavailability ; pharmacodynamics ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Six healthy volunteers received single iv and oral doses of 2-[p-(1-oxo-2-isoindolinyl)phenyl] butyric acid 100 mg (indobufen; K 3920), an inhibitor of platelet aggregation. Plasma levels and urinary excretion of the drug were determined by GLC. Collagen-induced platelet aggregation was assessed turbidimetrically at various intervals after administration. The plasma half-life of the drug was 7–8 h and more than 70% of the administered dose was recovered within 48 h in urine, as unchanged drug and as the glucuronide of indobufen. After oral administration of tablets of two different formulations, the drug was completely absorbed, but one formulation showed faster absorption. The maximal inhibitory effect on platelet aggregation was observed 1 to 4 h after iv administration, and it had decreased by 8 h. After tablets, peak effect and the time of the peak were similar, but activity was significantly prolonged, in accordance with the higher plasma levels found at 8 h. The data suggest that the effect of indobufen on platelets is reversible, and that for this drug platelets behave as a compartment that slowly equilibrates with plasma.
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  • 45
    ISSN: 1432-1041
    Keywords: myasthenia gravis ; neostigmine ; gas chromatography-mass spectrometry ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary To permit rational evaluation of the empirical pharmacotherapy of myasthenia with cholinesterase inhibitors, a sensitive and selective method for the determination of neostigmine has been developed. Analysis is based on ion-pair extraction of neostigmine into methylene chloride and determination by gas chromatography-mass spectrometry (chemical ionization). As neostigmine was found to be metabolized in plasma in vitro, deuterated (d6) neostigmine was immediately added to the plasma sample as the internal standard. The limit of quantitation of the method was about 1 ng/ml (∼ 3nmol/l). The kinetics following i. v. administration were studied in four patients, who received neostigmine 2.5–3.0 mg iv to antagonize pancurone administered during anaesthesia. Elimination was rapid with a half-life t1/2 (β-slope) of 0.89±0.05 h (mean ± SE). The volume of distribution was 1.08±0.11 l/kg and plasma clearance was 0.84±0.04 l/kg/h. In three fasting myasthenic patients plasma concentrations of neostigmine were followed for 5 h after a single oral dose of 30 mg. Considerable interindividual differences in absorption were expressed in the peak concentrations, which occurred 1–2 h following drug ingestion. The bioavailability of neostigmine was estimated to be 1–2% of the ingested dose. Neostigmine concentration in plasma was found to differ considerably (up to forty-fold) between myasthenic patients on their ordinary dose-schedules of cholinesterase inhibitors.
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  • 46
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    European journal of clinical pharmacology 15 (1979), S. 433-441 
    ISSN: 1432-1041
    Keywords: cyclobarbital ; barbiturates ; pharmacokinetics ; drug interaction ; volunteers ; patients
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The disappearance of cyclobarbital from plasma has been followed in healthy volunteers and in neurological and psychiatric patients after oral administration of one tablet of Phanodorm®, containing cyclobarbital calcium 200 mg. Plasma levels were measured by a thin-layer chromatographic method with in situ densitometry. The average t1/2 in healthy female and male volunteers was 13.3 h, and with the assumption of complete availability a mean distribution coefficient of 0.69 l/kg−1 and a clearance of 40.4 ml/min−1 were calculated. Repeated experiments in seven volunteers revealed good reproducibility of all values. When the healthy volunteers were combined with a group of untreated epileptics, a dependence of t1/2 and of the apparent volume of distribution on age was found, while clearance did not change with increasing age (range 17–54 years). Long half-lives caused by low clearance values were observed in several individuals with moderate obesity. No consistent change in cyclobarbital kinetics followed acute exposure of volunteers to alcohol or on treatment of neurological patients with carbamazepine. Patients under treatment with perazine exhibited more or less normal kinetic values. In terms of drug interaction, cyclobarbital differs from phenazone in several respects, and so it may prove a useful additional substance for measurement of the rate of drug oxidation in humans.
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  • 47
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    European journal of clinical pharmacology 16 (1979), S. 23-29 
    ISSN: 1432-1041
    Keywords: valproate ; epilepsy ; pharmacokinetics ; drug interaction
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In four refractory epileptic patients, peak plasma levels of sodium valproate occurred within 1.5 to 3 h after a single oral dose of valproate and the decline in plasma levels followed a monoexponential course with a t1/2 of 11.4 ± 0.1 h. The mean value for apparent volume of distribution was 0.176 ± 0.013 l/kg and for total plasma clearance 0.0106 ± 0.0009 l/h/kg. Steady state plasma levels were predicted using the method of superposition utilizing pharmacokinetic parameters determined following a single dose of valproate and were 78–123% of the predicted values for two patients receiving valproate alone, and 37–64% of the predicted values for the two patients receiving carbamazepine in addition to valproate. In a further group of 20 patients the mean daily doses of valproate for 8 patients receiving valproate alone (25.4 ± 4.9 mg/kg) was significantly less than those for the 12 patients receiving concomitant anticonvulsant therapy (41.6 ± 12.3 mg/kg) (p〈0.005). In addition, the steady state predose plasma levels of valproate were significantly higher in the valproate alone patients (90.3 ± 8.7 µg/ml) compared to the patients receiving additional anticonvulsants (75.3 ± 13.8 µg/ml) (p〈0.01). The higher dose requirements of valproate and lower predose and steady state plasma levels for those patients on multiple anticonvulsants indicate an interaction between valproate and other anticonvulsants.
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  • 48
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    European journal of clinical pharmacology 16 (1979), S. 133-139 
    ISSN: 1432-1041
    Keywords: theophylline ; asthma ; pharmacokinetics ; children
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Six children, aged 2 months – 4 years, received theophylline 5–6 mg/kg intravenously. Its disposition could be described by a two-compartment open model, the mean serum half life (t1/2 β) was 3.75 h, i. e., shorter than in adults, but there was a considerable interindividual variation (1.8–7.0 h, in one patient 13.3 h). Thirteen children (2 months – 4 years) received theophylline suppositories in a dose of 3.8–5.0 mg/kg, and ten (6 months – 4 years) in a dose of 8.4–14.5 mg/kg. Absorption was slow (mean half-time 43 min), incomplete and variable (biological availability 8–100%, mean 80%). Only four of the patients given the higher dose and none given the lower dose reached a therapeutic serum concentration (10–20 µg/ml). Nine children (6 months – 4 years) received rectal enemas of theophylline 4.1–9.2 mg/kg. Absorbtion was rapid (mean half-time 5.5 min) and biological availability averaged 100%. Six patients reached a serum concentration within the therapeutic range. Using the mean values of the calculated pharmacokinetic parameters, rectal enemas providing a dose of theophylline of 6–8 mg/kg t. i. d. were computed to give serum concentrations between 8–20 µg/ml, without producing too high a level during the absorption phase.
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  • 49
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    European journal of clinical pharmacology 16 (1979), S. 177-181 
    ISSN: 1432-1041
    Keywords: prazosin ; alpha receptor blockade ; blood pressure ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics and effects of prazosin have been studied after intravenous and oral dosing (1 mg) to 6 normal male volunteers. The mean terminal (β) half-life was 2.9 h after intravenous and oral routes. Oral bioavailability was 56.9%. The effects of prazosin on blood pressure were more pronounced after intravenous than oral administration, and the hypotensive effect greater on erect blood pressure. There was a significant correlation (P〈0.02) between the fall in blood pressure and the plasma drug concentration after intravenous prazosin.
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  • 50
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    European journal of clinical pharmacology 16 (1979), S. 243-249 
    ISSN: 1432-1041
    Keywords: timolol ; beta blockade ; pharmacokinetics ; pharmcodynamics ; acute administration ; chronic administration
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics and effects of various oral doses of timolol administered either acutely or after chronic medication for 7 days were studied in healthy volunteers. After acute administration of timolol maximum plasma concentrations were attained within 1–2 h and thereafter declined exponentially with time. The mean apparent half-life of elimination from plasma was 2.5 h and was independent of dose. Area under the plasma concentration-time curve (AUC) was proportional to the orally administered dose. Plasma concentrations, apparent elimination half-life and AUC were not altered after one week of chronic administration. The effect of timolol on heart rate and blood pressure response to three sequentially increasing ‘steady state’ work loads were studied. After acute administration of timolol maximum reduction of systolic blood pressure, resting heart rate, and the different parameters of the work-heart rate (or blood pressure) relationships were produced by 5 mg timolol. Increasing the dose prolonged the duration over which these variables were reduced. The relationship between timolol plasma concentration and inhibition of different parameters of the exercise response was hyperbolic with half maximum inhibition at concentrations of about 3–4 ng/ml of timolol and maximum inhibition above 30 ng/ml. Maximum drug effects and duration of action of timolol on the different variables were similar after acute and chronic administration.
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  • 51
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    European journal of clinical pharmacology 16 (1979), S. 327-330 
    ISSN: 1432-1041
    Keywords: atenolol ; food intake ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The influence of food intake on the bioavailability of the beta-adrenoceptor blocker atenolol was assessed by measurement of its single-dose kinetics in ten healthy volunteers, who took 100 mg both in the fasting state and together with a standardized breakfast. Food intake significantly shortened the time to reach peak concentration (2.7 h vs 1.5 h), but caused a significant reduction in AUC values, the mean decrease being 20%. The elimination half-life was unaffected. Atenolol, which is relatively hydrophilic, is incompletely absorbed in the fasting state, and escapes first-pass metabolism. The present findings indicate that food intake causes further impairment of its absorption, even though the absorption rate may initially be enhanced. This contrasts with previous observations on the more lipophilic beta-adrenoceptor blockers propranolol and metoprolol.
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  • 52
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    European journal of clinical pharmacology 16 (1979), S. 331-334 
    ISSN: 1432-1041
    Keywords: netilmicin ; radioenzymatic assay ; drug accumulation ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of a single dose of netilmicin (NM) was studied in 6 healthy volunteers. Elimination of the drug was followed in serum and urine for 24 h and 72 h, respectively. NM concentrations were measured with a modified radioenzymatic assay. A three compartment open model was employed to calculate the pharmacokinetic parameters. Following the rapid initial distribution, biphasic elimination with half lives of 1.99 h (t1/2β) and 36.89 h (t1/2γ) was demonstrated. Measurable amounts of NM were excreted in the urine for up to 72 h. The volume of distribution at steady-state (Vdss) of 0.68 l/kg was 3 to 4 times larger than previously reported for this antibiotic. NM plasma clearance was 91 ml/min and the renal clearance was 67 ml/min. The data indicate that on repetitive dosing the amount of drug in the body would be considerably underestimated if the prolonged terminal elimination phase were not taken into account. During prolonged treatment, accumulation of NM in renal and other tissues is likely to occur, as has been described for other aminoglycosides. The possible consequences of this pharmacokinetic behaviour are discussed.
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  • 53
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    European journal of clinical pharmacology 16 (1979), S. 335-340 
    ISSN: 1432-1041
    Keywords: cimetidine ; enterohepatic circulation ; irregular absorption ; bioavailability ; pharmacokinetics ; volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The bioavailability and pharmacokinetics of cimetidine have been studied in healthy volunteers after administration of single intravenous (100 mg) and oral doses (100, 400 and 800 mg). After i.v. administration, the kinetics of cimetidine could be described by a linear, two compartment open model. Substantial variation in half-life was observed between subjects, with a mean value of 2.1 h (range 0.9–4.7). Cimetidine had a low hepatic extraction ratio and a high total plasma clearance, due to extensive urinary excretion of unchanged drug. After oral administration, the plasma concentration vs time curves in most subjects exhibited two marked peaks, an observation that seemed to be constant within individuals and was independent of dose. Bioavailability, estimated as the area under the plasma concentration vs time curves (AUC), after oral doses as compared to the intravenous dose, in most cases exceeded 100%. There was no correlation between bioavailability estimated as AUC and as urinary excretion of unchanged drug. These observations may indicate an enterohepatic circulatory mechanism, predominantly after oral administration. Both unchanged drug and its sulphoxide metabolite appear to be excreted in bile. The latter was shown in vitro to be reduced to cimetidine by fecal bacteria.
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  • 54
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    European journal of clinical pharmacology 16 (1979), S. 411-416 
    ISSN: 1432-1041
    Keywords: doxapram ; intravenous infusion regimen ; pharmacokinetics ; data-point weighting ; healthy subjects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of intravenous doxapram in healthy individuals is consistent with a three-compartment open model. Doxapram was administered by bolus injection (1.5 mg · kg−1) and by intravenous infusion (6.5 mg · kg−1 for 2 h) to 5 subjects on separate occasions. There was no significant difference in mean terminal plasma half-lives (355 and 448 min) or in mean total body clearances (5.9 and 5.6 ml · min−1 · kg−1) following i. v. bolus injection or infusion respectively. In 3 subjects plasma doxapram concentrations during and after i. v. infusion agreed with those predicted from pharmacokinetic values obtained from the bolus injection study. Since mean steady-state concentrations (9.9 µg · ml−1) would be reached only after an extended interval (mean 15.2 h), a variable-rate infusion regimen was calculated to produce and maintain a concentration of 2 µg · ml−1 from 15–25 min onwards. A regimen in which the infusion rate is reduced step-wise is recommended to achieve early near-constant plasma doxapram concentrations.
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  • 55
    ISSN: 1432-1041
    Keywords: metoprolol ; tachycardia ; healthy subjects ; conventional tablets ; slow release tablets ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Plasma levels and associated reduction in exercise-induced tachycardia have been examined following the administration of single doses of metoprolol in conventional and slow-release tablets at different times to six healthy male subjects. The study was carried out in two parts. Initially, the tablets were given at 9 a. m. and the subjects were studied up to 14 h and then at 24 h. Subsequently, the same doses were given at 9 p. m. and the subjects were studied 12–24 h after drug administration (i. e. 9 a. m.–9 p. m. the next day). After giving the slow-release tablets the peak plasma levels were significantly lower but the drug persisted in the plasma at higher levels than after the conventional tablet. However, the beta-blocking effect was comparable from the two dosages. The results obtained for the period 12–24 h after the evening dose differed from the corresponding values after morning administration in that the plasma levels were higher and the betablocking effects more marked. Furthermore, the half-life values calculated from these data were significantly longer.
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  • 56
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    European journal of clinical pharmacology 15 (1979), S. 153-157 
    ISSN: 1432-1041
    Keywords: cimetidine ; renal failure ; elimination half life ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The plasma concentration curve after a single oral dose of cimetidine 200 mg was followed in 27 patients with varying degrees of chronic renal failure (creatinine clearance 1–52 ml/min) and in 46 patients with normal serum creatinine. Compared to the latter patients, the plasma concentration was higher and the elimination rate was slower in all uraemic subjects, including a group with moderate renal impairment. The preliminary recommendations of dosage for patients with a creatinine clearance below 5 ml/min, and for patients on regular haemodialysis, is cimetidine 200 mg every 12 h, 5–15 ml/min 200 mg every 12 to 8 h, 15–30 ml/min 200 mg every 8 h and 30–52 ml/min 200 mg every 6 h.
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  • 57
    ISSN: 1432-1041
    Keywords: nitrazepam ; epilepsy ; age ; disease ; plasma concentration ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Plasma concentrations of nitrazepam were measured by gas-liquid chromatography in: young healthy volunteers, in geriatric and psychiatric patients and in epileptic children. The disposition of nitrazepam was described in terms of a two-compartment open model. After a single oral dose of nitrazepam 5 mg the most prominent differences between the experimental groups were in the β-phase half-life-mean 29 h in the young volunteers and 40 h in geriatric patients, and in the apparent volume of distribution during the β-phase of 2.4 vs 4.8 l/kg. Total plasma clearance and the average steady state concentration in both groups were equal. The plasma level rose at a rate proportional to the β-phase half-life, and so, they were achieved more rapidly in the young than in the old subjects (3.5 vs 7.5 d). No change in steady-state level or in the half-life of nitrazepam were found during long term treatment, which indicates lack of enzyme induction or inhibition. In 95% of the epileptic children with a good to fair clinical response, the plasma concentration of nitrazepam was 40–180 ng/ml (mean 114 ng/ml). As all of the patients were on combined antiepileptic therapy, no attempt was made to correlate plasma level with therapeutic response.
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  • 58
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    European journal of clinical pharmacology 15 (1979), S. 257-261 
    ISSN: 1432-1041
    Keywords: cimetidine ; H2-receptor antagonist ; aging ; single dose ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The blood level versus time curve for unchanged cimetidine after a 200 mg oral dose has been determined in 20 apparently healthy subjects, ranging from 22 to 84 years of age. A significant relationship between the area under the curve (AUC) and age was found (r=0.81; P〈0.001). The peak concentrations of cimetidine were significantly inversely related to body weight (r=−0.71; P〈0.001). The age-related increase in bioavailability of oral cimetidine, as measured by AUC, was probably due to decreased total clearance of the drug, which resulted from the opposed changes (by themselves not significant) of distribution volume towards a decrease and of half-life towards an increase with age. Reduction in the standard oral dose of cimetidine by one third to one half should be feasible in the elderly without loss of efficacy, and it may be advisable in order to obviate extreme individual responses that may occur in this population.
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  • 59
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    European journal of clinical pharmacology 15 (1979), S. 275-280 
    ISSN: 1432-1041
    Keywords: Parkinson's disease ; bromocriptine ; pharmacokinetics ; plasma concentration
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The plasma kinetics of bromocriptine (BCT), a long-acting dopamine agonist, was studied in twelve patients with Parkinson's disease, using a newly developed gas chromatographic method of analysis. Each patient received BCT for at least three weeks in a constant but different dose regimen. Concomitant treatment with 1-DOPA was not allowed. During a 6-day hospitalization period, a blood sample was taken immediately before the afternoon dose at 14.00 h (Cmin) to determine the steady-state level. On the 6th day blood samples were collected every hour during two 8 h dose intervals. The results showed a significant correlation between the mean values of the AUC and the Cmin. First order elimination kinetics appeared to be followed by BCT, at least for the plasma concentrations commonly found. Considerable inter-individual variation was demonstrated both for the dose/plasma concentration ratio and for calculated plasma clearances. No serious side-effects were observed during the investigation.
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  • 60
    ISSN: 1432-1041
    Keywords: indobufen ; platelet aggregation ; food effect on bioavailability ; repeated administration ; pharmacodynamics ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effect of food on bioavailability of indobufen tablets was investigated in 6 healthy volunteers. Subsequently, the same subjects took 100 mg b.i.d. for 7 days. Plasma levels and urinary excretion of indobufen were determined by GLC. Platelet aggregation induced by several concentrations of adrenaline was determined turbidimetrically at various times after the first and last doses. The absorption of indobufen tablets was not substantially impaired by the presence of food in the GI tract, although peak plasma levels and AUCs were slightly reduced after food. Pharmacokinetic analysis of plasma and urinary levels of indobufen did not indicate any change in drug disposition after repeated dosing. Adrenaline-induced platelet aggregation was markedly inhibited for up to 12 h after the first dose and the intensity and duration of this effect did not change after repeated administration. A twice-daily dosing appears suitable for clinical trials.
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  • 61
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    European journal of clinical pharmacology 15 (1979), S. 341-347 
    ISSN: 1432-1041
    Keywords: clofibrate ; chlorophenoxyisobutyric acid ; disposition ; hepatitis ; cirrhosis ; renal failure ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The disposition of clofibrate over 96 hours was observed following single oral dose in six patients with acute viral hepatitis, six patients with liver cirrhosis, seven patients with renal insufficiency, and six control subjects. No parameter of the disposition of CPIB (active form of clofibrate) was significantly altered in acute hepatitis. In liver cirrhosis, the mean plasma half-life was unchanged compared to controls (20.9 vs. 17.5 h), but plasma clearance of the non-protein bound drug was reduced (115 vs. 243 ml×min−1), plasma protein binding was reduced (92.8 vs. 97.2 percent), and the apparent volume of distribution was increased (0.20 vs. 0.141×kg−1). In renal insufficiency plasma half-life was prolonged 2 to 6-fold, depending on the degree of renal impairment. Total plasma clearance (3.4 vs. 7.1 ml×min−1) and plasma clearance of the unbound drug (81 vs. 243 ml×min−1 were reduced in patients with renal failure, the clearance of the unbound drug being inversely correlated with the serum creatinine concentration. Renal failure was also associated with decreased protein binding and an increased volume of distribution of CPIB, and with reduced urinary excretion of CPIB and its glucuronide metabolite. The dose of clofibrate should be halved in patients with cirrhosis. In renal insufficiency, the dose should be adjusted according to the individual serum creatinine level: only 10 to 15% of the usual weekly dose should be given in complete renal failure.
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  • 62
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    European journal of clinical pharmacology 15 (1979), S. 363-366 
    ISSN: 1432-1041
    Keywords: methotrexate ; protein binding ; ultrafiltration ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The protein binding of methotrexate by serum from eight normal volunteers was assessed by continuous ultrafiltration at pH 7.4 and 37°C. Methotrexate concentrations were measured by radioimmunoassay and the data analysed by the method of Scatchard. The major binding protein was albumin which bound 87.3% of the drug in serum. Analysis of the Scatchard plots indicated two distinct groups of binding sites. Class I was found to have 0.16±0.05 (S D) binding sites with an intrinsic association constant of 71.15±35.98 (S D)×104 M−1: Class II had 2.01±0.93 (S D) binding sites and an affinity of 0.18±0.15×104 M−1. No great change in the percentage of methotrexate bound occurred until the total concentration of the drug exceeded 50 µMol 1−1.
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  • 63
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    European journal of clinical pharmacology 16 (1979), S. 1-6 
    ISSN: 1432-1041
    Keywords: lorcainide ; ventricular premature beats ; plasma levels ; pharmacokinetics ; side effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The plasma level and antiarrhythmic effect of lorcainide (R 15889) have been investigated in 15 patients with ventricular premature beats (VPB). Therapy was initiated with an intravenous dose of 1.9 mg/kg given over 10 min, followed by a constant infusion of 0.18 mg/kg/h for 24 h. In 8 patients the corresponding doses were increased to 2 mg/kg and 0.27 mg/kg/h. After the intravenous doses patients were treated orally with 100 mg tid for 6–7 days. The two dosage regimens were selected so as to achieve theoretical steady-state plasma levels (css) of 200 and 300 ng/ml, respectively. The combined intravenous treatment approached (181 ± 6.8 ng/ml and 273±28.5 ng/ml, respectively) the desired css within 2 to 4 h. During the oral administration, the minimal plasma concentrations following the lower intravenous dose (184±18 ng/ml) were significantly (p=0.0001) lower than after the higher intravenous dose (264±20.5 ng/ml). The dealkylated metabolite of lorcainide was not detectable after the intravenous doses, but it accumulated during oral treatment, when its concentration exceeded that of the parent compound. In 5 of the 7 patients receiving the lower dose VPB were effectively reduced. However, in only 4 of the 8 patients on the higher dosage schedule could a significant antiarrhythmic effect be demonstrated. In addition, side effects were observed in 6 of the subjects.
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  • 64
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    European journal of clinical pharmacology 16 (1979), S. 189-194 
    ISSN: 1432-1041
    Keywords: sparteine ; pharmacogenetic defect ; defective metabolism ; pharmacokinetics ; renal excretion
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Sparteine is metabolized by N1-oxidation, which in some subjects is defective. The defect has a pronounced effect on the kinetics of the drug. In non-metabolisers elimination of sparteine proceeds entirely via renal excretion by a capacity-limited process, 99,9% of the dose being excreted as unchanged drug. In metabolisers the drug is mainly eliminated by metabolic degradation. Pronounced differences in β-phase half-life and total plasma clearance were observed between metabolisers (156 min; 535 ml · min−1) and nonmetabolisers (409 min; 180 ml · min−1).
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  • 65
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    Journal of cancer research and clinical oncology 95 (1979), S. 83-86 
    ISSN: 1432-1335
    Keywords: 2-Chloroethylnitrosoureas ; Carcinogenesis ; Rat ; 2-Chloroethylnitrosoharnstoffe ; Carcinogenese ; Ratte
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Zusammenfassung Nach Heilung der akuten Rattenleukämie L 5222 bei 79 BD IX Ratten mit einmaligen Dosen von 1,3-bis(2-Chloroethyl)-1-nitrosoharnstoff (BCNU) oder 1-(2-Hydroxyethyl)-3-(2-Chloroethyl)-3-nitrosoharnstoff (Hydroxyethyl-CNU) entwickelten sich bei insgesamt 9 Tieren (∼ 11%) sekundäre Malignome.
    Notes: Summary After cure of rat leukemia L 5222 in 79 BD IX rats by single doses of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) or 1-(2-hydroxyethyl)-3-(2-chloroethyl)-3-nitrosourea (Hydroxyethyl-CNU) a total of 9 rats (11%) developed secondary malignomas.
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  • 66
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    Acta neuropathologica 47 (1979), S. 131-137 
    ISSN: 1432-0533
    Keywords: Rat ; Cerebellar cortex ; Protein deprivation ; Vessels ; Morphometry
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The postnatal vascular growth in the cortex of vermis cerebelli folium IX of normal and pre- and postnatally protein-deprived rats was examined. The rate of increase in specific length of vessels seem to parallel the functional maturation of neurons in all cortical layers. From the first postnatal week there is a higher specific length of vessels in the Purkinje cell layer than in the adjoining parts of the molecular and granular layers. The results indicate that such differences are present also after the period of rapid vascular growth. Protein deprivation appears to affect the postnatal increase in specific length of vessels less in the Purkinje cell layer than in the granular and molecular layer where a significant reduction compared to controls was seen for the interval 7–20 days of age. At 90 days of age no significant differences were seen between control and protein-deprived rats.
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  • 67
    ISSN: 1432-0533
    Keywords: Perineurium ; Protein deprivation ; Rat ; Peripheral nerve ; Diphtheria toxin
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Diphtheria toxin was locally administered around the sciatic nerves of normal and protein deprived rats aged 3, 6, 12, and 26 weeks in order to investigate the permeability of the barriers enveloping the nerves. At all ages the rats developed a reversible hind limb paralysis linked to a severe segmental demyelination, indicating passage of the toxin into the endoneurium. From 6 weeks of age the pattern of reaction differed between the protein deprived and control rats. The differences are discussed and interpreted as being partly dependent on less efficient protective barriers of the sciatic nerves of the protein deprived rats.
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  • 68
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    Acta neuropathologica 47 (1979), S. 33-37 
    ISSN: 1432-0533
    Keywords: Pexid (perhexiline maleate) ; Abnormal inclusions ; Retina ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Three morphologically distinct kinds of cytoplasmic inclusion (lamellar, reticular and crystalloid) developed in the retinal cells of suckling rats treated with Pexid (300 mg/kg/day). Lamellar inclusions were most abundant and they were seen in all types of retinal cells. This variety of inclusion was especially numerous in the ganglion cells. Reticular inclusions were encountered less commonly than the lamellar type and their distribution did not show any particular cellular predilection. Crystalloid inclusions were observed only in the pigment epithelial cells. The mechanism of formation of the three types of inclusion is not known, nor is the reason why certain types of inclusion occur most commonly in a particular kind of cell. One can speculate, however, that the dissimilarity of form may reflect differences in the metabolism and physicochemical properties of the various retinal cells.
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  • 69
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    Psychopharmacology 64 (1979), S. 113-120 
    ISSN: 1432-2072
    Keywords: 5,6-Dihydroxytryptamine ; Prostaglandins ; Behavior ; Hyperthermia ; Hypertension ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Ten days after administration of 5,6-dihydroxytryptamine, which causes degeneration of central serotoninergic neurons, the depressive behavioral effects of PGF2α and PGE2 were evidently inhibited. Central chemical serotoninectomy abolished the hyperthermic and hypertensive effects of PGF2α, but only slightly affected those of PGE2. It is concluded that serotoninergic neurons mediate the depressive behavioral action of both PGF2α and PGE2. They also mediate the hyperthermic and hypertensive action of PGF2α but not of PGE2. This suggests that these prostaglandins have different central modes of action.
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  • 70
    ISSN: 1432-2072
    Keywords: Clonidine ; Brain 3-methoxy-4-hydroxyphenylglycol ; Withdrawal syndrome ; Rat ; Bipolar depression
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The effect of clonidine withdrawal on the brain norepinephrine system was studied in the rat. Clonidine suppresses brain total 3-methoxy-4-hydroxyphenylglycol (MHPG) significantly and no tolerance to this effect was observed up to 21 days. Cessation of clonidine treatment resulted in an elevation in the level of brain total MHPG. The suitability of the clonidine withdrawal syndrome as a model of bipolar depression is discussed.
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  • 71
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    Psychopharmacology 65 (1979), S. 137-140 
    ISSN: 1432-2072
    Keywords: Male sexual behavior ; Rat ; Monoamines ; Thioridazine ; Chlorimipramine
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Thioridazine (3 mg/kg) and chlorimipramine (1.5–6.0 mg/kg) prolonged the ejaculation latency and increased the number of mounts but did not change the number of intromissions preceding ejaculation. Blockade of peripheral and central noradrenaline receptors by phentolamine and phenoxybenzamine respectively resulted in a suppression of all aspects of the sexual behavior with increasing doses. dl-5-HTP (25–100 mg/kg) in combination with an inhibitor of peripheral 5-HTP decarboxylase (benserazide, 25 mg/kg) produced, like chlorimipramine and thioridazine, a prolongation of ejaculation latency and an increase in the number of mounts preceding ejaculation. Selective inhibition of 5-HT reuptake however, by zimelidine (0–20 mg/kg) or alaproclate (0–20 mg/kg) did not affect the mating behavior. At higher doses of these drugs some animals failed to initiate sexual activities. There was an increase in the postejaculatory interval but no change in the ejaculatory latency. It is concluded that the prolonged ejaculation latencies observed following treatment with thioridazine or chlorimipramine is not due to a blockade of central or peripheral adrenergic α-receptors.
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  • 72
    ISSN: 1432-2072
    Keywords: Naloxone ; Potentiation ; DMT ; LSD ; FR4 operant behavior ; Rat ; Brain ; Liver
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The narcotic antagonist naloxone was tested to determine its possible interaction with N,N-dimethyltryptamine (DMT) and lysergic acid diethylamide-25 (LSD) in adult male Holtzman rats trained to press a bar on a fixed-ratio four schedule (FR4), i.e., every fourth press earned a reward of 0.01 ml sugar sweetened milk. LSD (0.1 mg/kg) or increasing doses of DMT (1.0, 3.2, and 10.0 mg/kg) were administered i.p. to disrupt food-rewarded fixed ratio bar pressing in a dose related fashion. Pretreatment (5–10 min) with behaviorally ineffective doses of naloxone (1.0–5.6 mg/kg) dramatically enhanced the effects of DMT and LSD. The content of DMT in the brain and liver of rats injected with DMT alone (10 mg/kg) and with a 5 min pretreatment of naloxone (3.2 mg/kg) was determined by radiochemical analysis at 30 and 90 min after 14C-DMT injection. There was no significant difference for either brain or liver 14C-DMT levels when control DMT rats were compared with the naloxone pretreated rats. These results seem to rule out interference by naloxone with the metabolism of DMT as a mechanism of the observed behavioral potentiation.
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  • 73
    ISSN: 1432-2072
    Keywords: β-Endorphin ; Morphine ; Enkephalin ; Catalepsy ; Antinociception ; Thermoregulation ; Rat ; Golden hamster
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The behavioral effects of β-endorphin, [D-Ala2, D-Leu5]-enkephalin and morphine were investigated in golden hamsters and in rats. In golden hamsters, β-endorphin and [D-Ala2, D-Leu5]-enkephalin induced loss of righting reflex, whereas morphine caused no such effect. Both opiate peptides and morphine caused the inhibition of tail-flick response and catalepsy in rats. β-Endorphin was the most potent, followed by [D-Ala2, D-Leu5]-enkephalin and then by morphine. The catalepsy induced in rats by [D-Ala2, D-Leu5]-enkephalin was different from that of β-endorphin and morphine in that it produced catalepsy without muscular rigidity. β-Endorphin and [D-Ala2, D-Leu5]-enkephalin caused hypothermia in golden hamsters; morphine was less active in altering the body temperature. β-Endorphin caused hypothermia at high doses and hyperthermia at low doses in rats. These heterogenous behavioral responses indicate that multiple types of receptors mediate the effects of opiates in the central nervous system.
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  • 74
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    Psychopharmacology 63 (1979), S. 311-312 
    ISSN: 1432-2072
    Keywords: Cocaine ; Spontaneous motor activity ; Stereotypy ; Behavioral interactions ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Effect of a single administration of a dose (5, 10, or 15 mg/kg, i.p.) of cocaine hydrochloride on spontaneous motor activity (SMA) and stereotypy (ST), and interactions between these behaviors were investigated in rats. SMA showed peak increases within 10 min and at 120 min after cocaine injection. Drug-induced stereotypy was maximal during the interval between these two peaks in SMA. Several neurotransmitters may be involved in the interactions between SMA and ST.
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  • 75
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    Psychopharmacology 63 (1979), S. 285-288 
    ISSN: 1432-2072
    Keywords: Ethanol ; Behavioral tolerance ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The roles of both reward and the amount of reinforced practice on the development of behavioral tolerance to ethanol were studied in 32 hooded rats in a Skinner-box situation. The effects of ethanol were evaluated on two aspects of the bar-press response (FR15): latency to complete 15 bar presses and proficiency to earn rewards. Results showed that the behavioral tolerance, as indicated by diminishing effects of ethanol on performances over repeated exposures, developed rapidly. The extent of the developed tolerance was greater and more stable in animals which had reinforced practice while under the influence of ethanol than in animals which had non-reinforced practice. Animals which were exposed to the same amount of ethanol but practiced the response in a nondrug state showed little sign of tolerance to ethanol. These findings give further support to a previous view that learning processes may be involved in acquisition of behavioral tolerance to ethanol.
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  • 76
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    European archives of oto-rhino-laryngology and head & neck 225 (1979), S. 185-190 
    ISSN: 1434-4726
    Keywords: Kallikrein ; Parotisspeichel ; Ratte ; experimenteller Hoch-druck ; Kallikrein ; Parotid saliva ; Rat ; Experimental hypertension
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Summary A technique for continuous and quantitative collection of parotid saliva — including salivary flow rate determination — for in vivo experiments in rats is described. Excretion of kallikrein-like activity in parotid saliva of rats with various forms of arterial hypertension (genuine, renovascular and DOCTMA-salt hypertension) was studied. Kallikrein excretion was measured by its esterolytic activity. The levels of kallikrein-like activity in parotid saliva of normotensive control rats ranged between 2.5–4.0 mU/min during salivary flow stimulation with pilocarpine. In all forms of experimental hypertension salivary excretion of kallikrein-like activity was increased 2–4 fold. This increase was not related to the activity of the renin-angiotensin system.
    Notes: Zusammenfassung Es wird eine Methode beschrieben für die fortlaufende, quantitative Untersuchung des Parotisspeichels von Ratten unter Berücksichtigung der Flußrate. Bei verschiedenen Formen des arteriellen Hochdruckes (genuiner, renovaskulärer, DOCTMA-Hochdruck) konnte so die Konzentration des Kallikreins im Parotisspeichel bestimmt werden. Die Kallikrein-Sekretion wurde gemessen an ihrer esterolytischen Aktivität. Die Exkretion des Kallikreins lag bei normotensiven Kontrolltieren zwischen 2,5 und 4,0 mU/min während einer durch Pilokarpin ausgelösten Stimulation der Drüsenfunktion. Bei allen Formen des arteriellen Hochdrucks war die Sekretion von Kallikrein um das zwei- bis vierfache erhöht. Dieser Anstieg hatte keine Beziehung zur Aktivität des Renin-Angiotensin-Systems.
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  • 77
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    Research in experimental medicine 176 (1979), S. 69-79 
    ISSN: 1433-8580
    Keywords: Skeletal muscle ; CO2-laser ; Surgery ; Ultrastructure ; Rat ; Skelettmuskelfaser ; CO2-Laser ; Chirurgie ; Ultrastruktur ; Ratte
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Zusammenfassung Der Zustand der dorsalen Haut und des darunterliegenden Muskelgewebes der Ratte wurde unmittelbar nach CO2-Laser-Schnitten mit Hilfe von licht- und elektronenmikroskopischen Methoden untersucht. In der subkutanen Skelettmuskelschicht konnte eine erhöhte Empfindlichkeit des Gewebes festgestellt werden, die in einer ausgeprägten Abfolge von Zellveränderungen ihren Ausdruck findet. Diese Schädigungen werden hauptsächlich den thermischen Effekten der Laserstrahlung zugeschrieben. Die Bedeutung dieser Untersuchungsergebnisse in Hinblick auf die Verwendung von Laser in der Chirurgie wird besprochen.
    Notes: Summary The immediate effect of CO2-laser incision to the dorsal skin and underlying muscular tissue of rats was studied by light and electron microscopical methods. In the subcutaneous layer of skeletal muscle cells an increased susceptibility was found, resulting in distinct zones of cellular changes which are attributed mainly to thermal effects of the laser beam. The importance of these findings for the surgical application of lasers is discussed.
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  • 78
    ISSN: 1573-8744
    Keywords: lorazepam ; benzodiazepines ; pharmacokinetics ; drug accumulation ; antipyrine
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Six healthy volunteers participated in single- and multiple-dose pharmacokinetic studies of oral lorazepam. Following single 4-mg oral doses, peak plasma lorazepam concentrations ranging from 40 to 70 ng/ml were reached within 3 hr of the dose. Values of absorption half-life averaged 25min (range 10.3–42.7min), and elimination half-life (t 1/2β ) averaged 14.2 hr (range 8.4–23.9 hr). During 15 consecutive days of 3 mg per day administered in divided doses, accumulation to the steady-state condition was complete within several days of the initiation of therapy. Values of accumulation half-life (mean 21.1 hr) were slightly longer than t 1/2β , and the two were not well correlated. Observed accumulation ratios (mean 1.88) were very close to those predicted from the single-dose study (mean 1.77), but the correlation between the two (r=0.51) was not significant in the small sample size. “Washout” half-life values (mean 14.9 hr) were highly correlated with t 1/2β (r=0.92). Clearance of a single intravenous dose of antipyrine determined prior to the multiple- dose lorazepam study (mean 0.86 ml/min/kg) was essentially identical to that determined after the study (mean 0.87 ml/min/kg). Overall, the rate and extent of lorazepam accumulation during multiple dosage were reasonably well predicted by the single-dose kinetic study. However, accurate prediction for any specific individual was not always achieved. Stimulation or inhibition by lorazepam of its own clearance probably does not explain imprecise prediction, since single-dose t 1/2β .
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  • 79
    ISSN: 1573-8744
    Keywords: digoxin ; pharmacokinetics ; response kinetics ; three-compartment model ; serum digoxin kinetics ; systolic time intervals ; radioimmunoassay
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract A study designed to investigate the relationship between the pharmacokinetics of digoxin and a measure of its pharmacological effect has been conducted. Serum digoxin concentrations and systolic time intervals were measured concurrently in 12 normal male volunteers following a 1.0 mg i.v. bolus injection. The averaged serum digoxin concentration- time and response-time data were analyzed pharmacokinetically using a three-compartment open model and nonlinear least- squares fitting. When only the serum level-time data were analyzed, a close relationship was found between calculated digoxin levels in the slowly distributing (deep) peripheral compartment and response of the heart to digoxin, as measured by changes in the QS2 index δQS2I. Although it was not possible to distinguish clearly a linear from a nonlinear relationship between digoxin levels in the deep compartment and δQS2I, the nonlinear relationship gave the best overall fit when both serum digoxin and δQS2I data were fitted simultaneously. The simultaneous fityielded a total body clearance of digoxin of 3.6 ml/min/kg and a terminal t1/2 of 42 hr.
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  • 80
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    Journal of pharmacokinetics and pharmacodynamics 7 (1979), S. 87-95 
    ISSN: 1573-8744
    Keywords: clonazepam ; in vivo biotransformation ; 7-amino metabolite ; pharmacokinetics ; monkeys ; anticonvulsants
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The pharmacokinetic behavior of the 7-amino metabolite of clonazepam administered exogenously and formed endogenously from the parent drug was studied in a group of rhesus monkeys using constant rate intravenous infusions. Plasma levels of the 7-amino metabolite and/or clonazepam were determined with a GC-CI-MS method. The biological half-life of the 7-amino metabolite (2.2 ± 1.0 hr) was shorter than that of clonazepam (4.9 ± 0.2 hr). Total body clearance of the metabolite (0.83 ± 0.16 liters/hr/kg) was larger than that of the parent drug (0.55 ± 0.09 liters/hr/kg). The kinetics of in vivo biotransformation were described by a two- compartment model in which formation and disposition of the metabolite follow first-order processes. The fraction of a dose of clonazepam appearing in the systemic circulation as 7-amino metabolite was 0.70 ± 0.30. This value may underestimate the actual fraction formed, if the metabolite is susceptible to first- pass metabolism following in situ formation.
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  • 81
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    Journal of pharmacokinetics and pharmacodynamics 7 (1979), S. 265-274 
    ISSN: 1573-8744
    Keywords: furosemide ; indomethacin ; prostaglandin ; pharmacokinetics ; pharma-codynamics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The pharmacokinetics and pharmacodynamics of intravenous furosemide, 40 mg, were studied in four normal males in a crossover fashion with and without indomethacin pretreatment. In each study 16 plasma and 10 urine samples were collected over 24 hr. Fluid and electrolyte urinary losses were replaced orally throughout the study. Unchanged furosemide and indomethacin were measured using HPLC; urinary sodium was measured by flame photometry. Pretreatment with indomethacin resulted in increased and prolonged furosemide plasma levels, increased area under the curve, decreased plasma clearance, decreased renal clearance, increased half-life, no change in volume of distribution, and decreased sodium excretion and urine volume. Analysis of sodium excretion rate with time shows that the inhibiting effect of indomethacin was greater during the first 2 hr than at later times.
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    Journal of pharmacokinetics and pharmacodynamics 7 (1979), S. 453-462 
    ISSN: 1573-8744
    Keywords: pheneturide ; antiepileptics ; pharmacokinetics ; TLC-UV densitometry
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The pharmacokinetics of pheneturide (a decarboxylation product of phenobarbital), used to prevent psychomotor seizures for many years, was studied in normal human volunteers. To measure the drug in plasma and urine, a highly sensitive and reproducible thin-layer chromatography-reflectance spectrophotometric assay was developed. The results show that pheneturide follows first-order kinetics in the dose range studied. Its half-life after single doses is 54 hr (range 31–90), and its total body clearance (100% nonrenal) is 2.6 liters/hr (range 1.73–3.59). After repetitive administration, half-life is 40 hr (but clearance remains unchanged because of a lower volume of distribution). Because of the long half-life, repetitive administration results in a continuous steady-state level and makes this drug (kinetically) ideal for long-term use.
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  • 83
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    Journal of pharmacokinetics and pharmacodynamics 7 (1979), S. 471-479 
    ISSN: 1573-8744
    Keywords: metoprolol ; α-OH-metoprolol ; active metabolites ; pharmacokinetics ; β- blocking effect
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The plasma levels and the β- blocking effect of metoprolol and its active metabolite α- hydroxymetoprolol have been studied after i.v. bolus injections of the substances to dogs. For both substances the β- blockade increased with the dose, and there was a linear relationship between percent reduction in exercise heart rate and the logarithm of plasma concentration. The dose of the metabolite, however, had to be 5 times higher than that of metoprolol to induce the same degree of β- blockade. Because of differences in the volume of distribution, 2.0 liters/kg for α- OH-metoprolol and 3.5 liters/kg for metoprolol, the 5 times higher dose of α- OH-metoprolol resulted in 10 times higher plasma levels of the metabolite than of metoprolol. α- OH-Metoprolol was more slowly eliminated (t1/2∼7.0 hr, total body clearance ∼3.5 ml-kg−1-min−1) than metoprolol (t1/2∼2.0 hr, total body clearance ∼20.0 ml-kg−1-min−1). Approximately 5% of an i.v. dose of metoprolol was metabolized to α- OH-metoprolol. The half-life of the endogenously formed metabolite was the same as after an i.v. dose of the compound.
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    Experimental brain research 34 (1979), S. 201-215 
    ISSN: 1432-1106
    Keywords: Intrahypothalamic connections ; Deafferentation ; Electron microscopy ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Terminal degeneration within the hypothalamus was studied by electron microscopy 1 or 2 days (1) after carefully placed microlesions in the arcuate, anterior periventricular, ventromedial, premammillary and posterior hypothalamic nuclei and (2) after microlesions placed in the hypothalamus deafferented 3 weeks earlier. In the median eminence terminal degeneration was found after each of these lesions. Projections from the ventromedial nucleus reach the arcuate, suprachiasmatic, and anterior periventricular nuclei. Projections from the arcuate nucleus terminate in the medial preoptic, anterior periventricular, and ventromedial nuclei. After lesioning the premammillary nuclei degeneration was found in the supraoptic, arcuate, anterior hypothalamic and ventromedial nuclei.
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  • 85
    ISSN: 1432-1106
    Keywords: Rat ; Fusimotor efferents ; Pinna stimulation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Pinna stimulation has long been known to evoke reflex changes of discharge in γ efferents to the hind limb and hence changes in muscle spindle discharges. The present experiments were made in the rat to determine the involvement of the static and dynamic fusimotor systems in the pinna reflex. We first observed fusimotor activity indirectly, by recording spindle responses to various length changes with and without concurrent pinna stimulation. Afferent responses were clearly influenced by static fusimotion during the reflex; evidence for dynamic fusimotion was sought but not found. Ipsilateral and contralateral stimuli appeared equally effective in evoking this static fusimotion. The magnitudes of afferent responses differed markedly between muscles. Observations were made simultaneously on activities recorded directly from γ efferents to peroneal and soleus muscles. Several γ efferents were spontaneously active in each nerve; pinna stimulation usually enhanced their activities and aroused also several others, previously quiescent. The frequencies of discharge in γ efferents to peroneus were usually higher than in those to soleus. This must in part be responsible for differences in afferent responses. The spontaneously active and activated fibres together formed about one quarter to one third of the total γ motoneurone pool and had conduction velocities restricted to the lower end of the conduction velocity spectrum for γ fibres.
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  • 86
    ISSN: 1432-1106
    Keywords: Hypothalamic paraventricular nucleus ; Spinal projection neuron ; Hypophyseal projection neuron ; Horseradish peroxidase ; Electron microscopy ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The distribution of labeled neurons in the paraventricular nucleus of the hypothalamus (PVN) was studied following injections of horseradish peroxidase (HRP) into the spinal cord (C8 to T1) or the hypophysis in the rat. Injections were also made in the spinal cord in another group of animals, which were subjected to water deprivation for a period of 3 days, and the PVN of these animals was examined with the electron microscope. Spinal projection neurons (paraventriculospinal tract, PVST, neurons) formed two groups; the dorsal and the ventral groups. They were located within the parvocellular part of the PVN and fused into one at the caudal level. The neurons of the dorsal group were well assembled whereas those of the ventral group were intermingled with paraventriculohypophyseal tract (PVHT) neurons, which were concentrated in the magnocellular part. Electron microscopic observations revealed that HRP-labeled neurons after spinal injections did not contain neurosecretory granules and that they were not affected by water deprivation. On the other hand, neurons containing a number of neurosecretory granules displayed a significant degree of dilatation of the endoplasmic reticulum as the result of water deprivation. These neurons contained no HRP granules. The present findings suggest that the PVST neurons are distinct from the PVHT neurons and that the neuronal groups of both systems form different cell columns within the nucleus.
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  • 87
    ISSN: 1432-1106
    Keywords: Rat ; Lateral geniculate nucleus ; Receptive fields ; Conduction velocity
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary 1. The receptive field properties and responses to electrical stimulation of 126 P-cells recorded from the dorsal lateral geniculate nucleus (LGNd) were studied in the hooded rat. 2. Eighty-five cells had a concentric (Kuffler, 1953) receptive field organisation (46 off-centre on-surround; 39 on-centre off-surround). Of the remaining cells 29 had co-extensive on/off excitatory discharge regions, nine had on-centres with suppressive surrounds and two cells gave on-responses but had no suppressive surround. One cell was identified as suppressed-by-contrast. 3. On the basis of the battery of tests developed for the identification of cell types in the cat's retina and LGNd, 35 of the cells with a Kuffler-type receptive field organisation were identified as Y-like. The majority of the remaining cells, both concentric and others, reminded us of the different subclasses of W-cells of the cat. Nine concentric cells in most of the tests exhibited X-like properties. 4. All of the Y-like cells were driven by relatively fast conducting retinal ganglion cell axons, comprising the t1 conduction velocity group. The majority of the remaining cells were driven by slower axons comprising t2 or t3 conduction velocity groups. 5. Thus, in the rat, as in other mammalian species studied so far, there is a correlation between the conduction velocity groups in the retino-geniculo-cortical pathway and the functional groups based on the cells’ receptive field properties. There seem to be functional equivalents of the cat's Y- and W-cell classes but evidence for a distinct X-like class of cells is lacking.
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  • 88
    ISSN: 1432-1106
    Keywords: Rat ; Hypoglossal nucleus ; Ultrastructure ; Second axotomy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The left hypoglossal nerve of adult male albino rats was prevented from regenerating to the tongue after a distal axotomy by implanting the proximal stump into normally innervated left sternomastoid muscle. Eighty-four days after implantation, the hypoglossal nerve was transected again and its regeneration to the tongue unimpeded. From 8 to 70 days after this second axotomy the left hypoglossal nuclei were processed for quantitative ultrastructural analysis. The first aim of this study was to compare regeneration success in the hypoglossal nucleus after second axotomy with that accompanying outgrowth of the hypoglossal nerve into denervated sternomastoid muscle. During quantitative analysis a second aim developed, of elucidating bouton/glial relationships. The second axotomy induced loss and return of subsurface cisterns, dispersal and reassembly of Nissl substance, increase and decrease of microglial numbers, slight further loss and partial return of boutons with clear spherical vesicles and symmetrical synapses, slight increase and decrease of boutons with clear flat vesicles and symmetrical synapses, regrowth of retracted dendrites and restoration of their synapses, and gradual diminution of numbers of electron-dense neurones and dendrites. Astrocytes remained hypertrophied throughout. When compared with events in the hypoglossal nucleus accompanying innervation of denervated sternomastoid muscle by the hypoglossal nerve, the results suggest (1) that regeneration of the hypoglossal nerve to its own tongue muscle instead of to a foreign muscle caused no acceleration of recovery in the hypoglossal nucleus, and (2) that the microglial response is dependent on nerve integrity and not on bouton behaviour.
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  • 89
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    Experimental brain research 36 (1979), S. 259-264 
    ISSN: 1432-1106
    Keywords: Micro application ; Drugs ; Nervous tissue ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary A method is described for localized microapplication of drugs into nervous tissue of freely moving rats. Fairly constant release of material was observed over a period of more than three weeks. The amount of substance released was small because the rate of release was determined largely by diffusion rather than by mass movement of solution.
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  • 90
    Electronic Resource
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    Experimental brain research 36 (1979), S. 343-357 
    ISSN: 1432-1106
    Keywords: Early stimulation ; Rat ; Brain chemistry ; Evoked potentials ; Learning and memory
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary A complex stimulation regimen (visual, auditory, and somesthetic-kinesthetic with forced movements, 30 times for 30 min each within 14 days) increased significantly the amplitudes of visual cortical evoked potentials (EPs) in adult rats if applied during the second postnatal fortnight. The EP increase after stimulation during the first 14 days after birth was not significant. Visual stimulation alone was compared with complex stimulation (visual plus forced movements) during the 2nd postnatal fortnight. More specific local changes in the visual cortex were revealed in brain biochemistry (lower DNA concentration, more RNA and protein per cell) and cortical electrogenesis (enhanced visual EPs) after visual stimulation alone, whereas complex stimulation induced more diffuse changes and rather profoundly influenced higher nervous functions (viz., memory retrieval — improved 24-h retention). Involvement of both specific and nonspecific mechanisms in the aftereffects of early stimulation is indicated.
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  • 91
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    Experimental brain research 36 (1979), S. 387-392 
    ISSN: 1432-1106
    Keywords: Rat ; Hypoglossal nucleus ; Boutons ; Glia ; Bungarotoxins
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Somatic bouton frequencies, and percent coverage of perikaryal circumference by boutons, microglia, astrocytes, or other structures, were measured on electron micrographs of the left hypoglossal nucleus of adult male albino rats after injections, into the left side of the tongue, of either α-bungarotoxin or β-bungarotoxin in a buffered saline solution (PBS). Control rats were injected with PBS alone. Values from bungarotoxin-treated rats were compared statistically with those from controls and normal rats. Somatic bouton frequencies and percent coverage of perikarya by boutons, were reduced in all the β-bungarotoxin-treated rats when compared with control or normal values. The control values were normal. In α-bungarotoxin-treated rats somatic bouton frequencies were reduced in four of the six rats, and percent coverage of perikarya by boutons in three of the six rats. A few microglia (up to 3.1% coverage) were present in β-bungarotoxin-treated rats, but none were found in α-bungarotoxin-treated rats, controls, or normals. Percent coverage of perikarya by astrocyte was significantly much higher than normal in bungarotoxin-treated rats, and higher than normal in the controls. Conversely, percent coverage by other structures was reduced in bungarotoxin-treated rats and controls. It is suggested that boutons and glia respond to different stimuli, and that the behaviour of the microglia is dependent on the condition of the hypoglossal nerve and not on bouton behaviour.
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  • 92
    ISSN: 1432-1106
    Keywords: Rat ; dLGN ; Retinal afferents ; X- and Y-channel ; Geniculo-cortical relay cells ; HRP
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary In the rat's dorsal lateral geniculate nucleus (dLGN) two types of retino-geniculate axon terminals have been visualized electron microscopically in adult and juvenile material as well as in Golgi-Kopsch and Golgi-Rapid impregnated sections. The two types differ in size and number of boutons. 2a-terminals have large, sparse boutons, mainly connected with branching zones of geniculo-cortical relay cells (GCR cells). 2b-terminals bear numerous small boutons forming simple contacts with more distal segments of GCR cell dendrites. We are not able to give any information about participation of either type in complex synaptic zones. After horseradish peroxidase (HRP) injection in the superior colliculus optic tract fibres and lateral fibre bundles in the dLGN are labelled with reaction product. Besides these tracts the terminal branching zones of retino-tectal fibre collaterals in the dLGN also show reaction product. As a result of the good visualization of these retinal terminals by the HRP-method they are identified as 2a-terminals. We conclude that 2a-terminals may represent the Y-channel projecting from the retina to both the superior colliculus and the dLGN.
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  • 93
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    International archives of occupational and environmental health 42 (1979), S. 141-148 
    ISSN: 1432-1246
    Keywords: Non-protein sulfhydryl concentration ; Liver ; Lung ; Kidney ; Blood ; Rat ; Human ; Glutathione
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The concentration of non-protein sulfhydryl compounds (NPSH) were measured at various times of the day in rat blood, liver, lung, and kidney as well as in human blood. In each of these cases, there was a significant (p 〈 0.05) 24 h concentration variation. The variation in rat liver non-protein sulfhydryl concentration, with a maximum around the noon-time period and a minimum around midnight, appeared to be related to food intake. Blood, lung, and kidney concentrations were not similarly related to food intake. No simple, linear correlation could be shown between tissue non-protein sulfhydryl concentration among the four rat tissues. Thus, rat blood NPSH does not predict rat tissue NPSH concentrations. In seven normal human volunteers, four males and three females, significant 24 h variations in blood NPSH concentrations were observed.
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  • 94
    ISSN: 1434-0879
    Keywords: cAMP ; Calcium metabolism ; Parathyroid hormone ; Ion-exchanger ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Rats received a diet containing a Cabinding ion exchanger at a dose of 30 and 90 g/kg diet, respectively. Following 10 days of oral administration there was a dose dependent increase in urinary cAMP excretion. However, after 20 days treatment the measured cAMP content in the urine was no longer different from control values. The results suggest that urinary cAMP excretion in the rat is only of value as an indication of acute changes in PTH-activity.
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  • 95
    ISSN: 1432-0878
    Keywords: Vomeronasal organ ; Membrane particles ; Cell contacts ; Freeze-etching ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Summary The free surfaces and cell contacts in the epithelia of the vomeronasal organ of the rat were investigated by freeze-etching. The microvilli of receptor cells show a lower density of intramembranous particles (IMP) than the microvilli in the receptor-free epithelium. The ratio between the IMP on P and E-face is approximately 11∶1 in the receptor terminals, and 3.5∶1 in the cilia and microvilli of the receptor-free epithelium. Although atypical in length and only poorly equipped with rootlet fibers, the cilia of the receptor-free epithelium are furnished with typical ciliary necklace structures of up to 10 rows of membrane particles. Differences in the density of IMP on the P-faces of different cilia are probably due to continual ciliogenesis and also due to the different age of cilia in the receptor-free epithelium. Zonulae occludentes show different configurations in the neuroepithelium and in the receptor-free epithelium. In the former, they show a tendency to cross-link and form facet-like patterns, reflecting a constant morphology and relative stability for this apical region. In the receptor-free epithelium the junctional rows of zonulae occludentes display only loosely interconnected networks and a tendency to orient parallel to each other and to the free surface. In addition to zonulae occludentes, typical square aggregations of IMP are observed in the receptor-free epithelium. They are not exclusively restricted to the zone of intensive cell contacts by means of fine interdigitating cell processes, and their function has yet to be identified experimentally.
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  • 96
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    Cell & tissue research 196 (1979), S. 147-151 
    ISSN: 1432-0878
    Keywords: Submaxillary salivary gland ; Secretory granules ; Glycoproteins ; Effect of heat ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Summary Secretory granule area and glycoprotein concentration of the saliva in the submaxillary gland of rats were measured during various stages of acclimation to heat at 34±1° C. Granule size decreased by 18% during the first five days of heat acclimation (0.025〈p〈0.05) after which period it increased to reach 118% of the control levels after 28 days (p〈0.05). Glycoprotein concentration in the saliva of stimulated glands rose above control levels, reaching a maximum between the 2nd and 5th day of acclimation (p〈0.05). It was concluded that the initial decrease in granule size reflects a decrease in glycoprotein content following an increase in salivary flow known to occur at high ambient temperatures. The subsequent increase in granule size is considered an adaptation of the gland to continuous stimulation. The rise in salivary glycoprotein concentration suggests increased efficiency of the secretory mechanism.
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  • 97
    ISSN: 1432-0878
    Keywords: Hypothalamus ; Median eminence ; Intraependymal cisternae ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Summary Structure, three-dimensional arrangement and ontogeny of large intracellular cisternae located in the median eminence region of the rat hypothalamus were studied using toluidin-blue stained semithin sections and electron microscopy. The cisternae occur along the projections of ependymal cells lining the ventral portion of the third ventricle (infundibular recess). Small cisternae can be seen close to the ventricle, whereas larger ones, divided into smaller compartments by thin septa, cluster near the surface of the hypothalamus. The cisternae are encompassed by a thin layer of cytoplasm to which axon terminals containing synaptic and dense core vesicles are closely related. Cisternae are arranged around the median eminence in a characteristic pattern. They occupy the midline in the retrochiasmatic area, flank both margins of the median eminence and extend caudally behind the origin of the pituitary stalk. The cisternae appear first between the 15th and 17th postnatal days. At about the 30th day their size and distribution resemble the situation observed in adult animals. The ependymal cisternae are suggested to be closely related to the luteinizing-hormone releasing-hormone (LH-RH)-containing fibers.
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  • 98
    ISSN: 1432-0878
    Keywords: Neurosecretion ; Hypothalamo-hindbrain pathway ; Rat ; Blood pressure ; Milk ejection
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Summary 1. In lactating rats and in rats deprived of water, the amount of neurosecretory material in the fibres of the neurosecretory hypothalamohindbrain pathway exceeds that in untreated control animals. Under these experimental conditions the pathway and its target regions can be well analysed by means of fluorescence and electron microscopic methods. 2. The axons belonging to the hypothalamo-hindbrain pathway originate from perikarya located in the caudal portion of the nucleus paraventricularis and also from a small group of perikarya in the caudo-lateral hypothalamus. On the way to the hindbrain the neurosecretory fibres join other fibre bundles of the mid- and hindbrain. 3. In the hindbrain most of the neurosecretory fibres terminate in the area of the nucleus tractus solitarii and in the area of the dorsal column nuclei. The axon terminals form synapses with other neurones. 4. Using cytochemical methods at the ultrastructural level (Naumann and Sterba, 1976), the authors were able to prove that the vesicles in the exohypothalamic fibres and in their synaptic terminals contain the same sort of material as the neurophysin vesicles in the posterior lobe of the hypophysis. 5. The most distinct increase in neurophysin was observed in lactating females which were separated from their sucklings after a normal lactation period of 15 days and killed four days thereafter, and in rats deprived of water for different time periods. 6. The relationship of the neurosecretory hypothalamo-hindbrain pathway to the nucleus tractus solitarii and to the dorsal column nuclei suggests that, functionally, there may be a correlation between the system of blood-pressure control and the milk ejection reflex.
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  • 99
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    Cell & tissue research 201 (1979), S. 93-99 
    ISSN: 1432-0878
    Keywords: Pituitary cell ; Gonadotrophs ; Culture ; Cell lines ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Summary Gonadotroph-rich cell lines were established from multipotential pituitary clonal cells (2A8) which were implanted under kidney capsule of hypophysectomized female rats. These cell lines secrete gonadotrophins (FSH and LH) continuously over two months after establishment; LHRH stimulated the secretion of hormones into the culture medium. Many of the cells reacted immunohistochemically to antiserum to FSH or LH, while a small number reacted to antiserum to prolactin or TSH. They did not contain normal secretory granules such as those of gonadotrophs in vivo.
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  • 100
    ISSN: 1432-0878
    Keywords: Hypothalamo-hypophysial system ; Rat ; Tanycytes ; Ontogeny
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Summary The differentiation of tanycytes was studied light and electron microscopically during the perinatal period in rats, the time when functional connections between hypothalamus and hypophysis are established. The 3rd ventricle is slit-like between 16 and 18 days of the prenatal period. Its wall is formed by intensively proliferating matrix cells with apical processes, ovoid perikarya and a basal process. The ventral region of the 3rd ventricle becomes funnel-shaped on the 20th day of the prenatal period. As the cells differentiate, the apical process becomes shorter and broader. Moreover, on day 20 of prenatal life cells without apical processes appear. Their number increases during the postnatal period. The concentration of endoplasmic reticulum, mitochondria, polysomes, lipid droplets, dense bodies (lysosomes), lamellated and multivesicular bodies increases. Initially the cells are similar but from the 3rd day of postnatal life differentiation occurs in different regions of the infundibular recess. After the 5th day, there are no marked changes in the structure and distribution of these cells.
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