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  • 1985-1989  (298)
  • 1965-1969
  • 1985  (298)
  • Rat  (203)
  • pharmacokinetics  (95)
  • 101
    Electronic Resource
    Electronic Resource
    Springer
    European journal of clinical pharmacology 28 (1985), S. 171-175 
    ISSN: 1432-1041
    Keywords: pethidine ; drug metabolism ; pethidine metabolites ; renal excretion ; pharmacokinetics ; geriatrics ; old age ; meperidine
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In a previous study old subjects were found to eliminate pethidine and its active metabolite norpethidine more slowly than young people. To investigate whether this was due to the decline in renal function with age, the urinary output of pethidine and its metabolites pethidinic acid, norpethidine and norpethidinic acid was compared in old and young patients. The cumulative urinary excretion of pethidine and pethidinic acid over 24 h was similar in old and young patients. The slower elimination rate of pethidine from plasma might therefore be due to slower biotransformation of pethidine to norpethidine and norpethidinic acid. The cumulative urinary excretion of norpethidine and norpethidinic acid during 24 h was significantly lower in old patients than in young: 2.7% versus 7.1% (p〈0.001), and 5.5% versus 10.5% (p〈0.001). The renal clearance of norpethidine was inversely correlated with age. Thus, the slower disappearance of norpethidine from plasma in old patients is due to slower renal excretion of this metabolite. The renal clearance of pethidine showed pH-dependence and was usually smaller than the creatinine clearance. In contrast, renal clearance of norpethidine was correlated with creatinine clearance and was of the same magnitude. The difference in renal handling may be explained by the more polar character of norpethidine compared to its parent compound. The present study shows that not only the excretion of unchanged drugs may decline with increasing age but also that of drug metabolites, which may therefore reach higher plasma levels in old patients. If they are pharmacologically active they will increase and prolong the response to medication and possibly increase the risk of side effects.
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  • 102
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    Springer
    European journal of clinical pharmacology 29 (1985), S. 215-219 
    ISSN: 1432-1041
    Keywords: penbutolol ; renal impairment ; beta-adrenoceptor blocking agents ; metabolism ; hypertension ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of penbutolol, its 4-hydroxylated metabolite and of their conjugates was studied in hypertensive patients with various degrees of renal impairment. A single oral dose of penbutolol 40 mg, was rapidly absorbed after a lag-time of 0.34 h. Its plasma concentration reached a maximum after 0.84 h and then declined bi-exponentially, with an apparent elimination half-life of 21.8 h. The hydroxylation of penbutolol was negligible and conjugation was of major importance for its elimination. Consequently, the kinetics of unchanged penbutolol were not altered by renal impairment. The 48 h-urinary excretion of penbutolol and its metabolites reached 13–14% of the administered dose, which is consistent with extensive metabolism of the drug. After treatment for 30 days with penbutolol 40 mg/d there was no accumulation of the parent drug but the concentration of its conjugates was increased. It is concluded that the dose of penbutolol need not be changed in patients with mild renal insufficiency, 4-hydroxypenbutolol is unlikely to participate in the anti-hypertensive effect of the drug, due to its low concentrations, and biotransformation of penbutolol may be enhanced during chronic treatment.
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  • 103
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    Springer
    European journal of clinical pharmacology 29 (1985), S. 221-224 
    ISSN: 1432-1041
    Keywords: fenfluramine ; norfenfluramine ; isomers ; pharmacokinetics ; healthy volunteers ; chronic treatment
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The kinetics of accumulation and elimination of d- and l-fenfluramine (F) and norfenfluramine (NF) have been studied in 8 young healthy volunteers given daily doses of 60 mg of sugar-coated tablets of 20 mg dl-F hydrochloride (dl-F) t.i.d. and capsules of 15 mg d-F hydrochloride (d-F) b.i.d. for 15 days. Repeated doses of d-F plus l-F gave the same values for the parameters measured as did d-F administered alone. Steady-state concentrations of all compounds were achieved within 4–8 days. The predicted mean steady-state concentrations of d-F and elimination half-lives calculated from the results of a previous single dose study were similar to those measured at steady state in this study, confirming the lack of effect of the drug on hepatic microsomal enzymes and on kinetics after repeated dosing. d-NF concentrations were approximately half those of the parent drug and the half-life was almost twice as long. Steady state concentrations both of L-f and l-NF were consistently about 40–50% higher than of the d-isomers and there was a comparable in the half-life.
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  • 104
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    European journal of clinical pharmacology 29 (1985), S. 323-329 
    ISSN: 1432-1041
    Keywords: lignocaine ; pharmacokinetics ; proteinbinding ; indocyanine green ; ageing
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Single dose studies were performed in six young and six elderly nonsmokers using lignocaine as a model drug with high intrinsic clearance. Subjects received lignocaine 250 mg orally and 50 mg intravenously in random order and drug concentrations in blood and plasma were measured for up to 8 h after dose. Protein binding was estimated at 37 °C by equilibrium dialysis. Indocyanine green kinetics were also calculated in each individual following 0.15 mg/kg intravenously. Bioavailability of lignocaine was greater in the elderly but there was no apparent difference in the rate of absorption. Intrinsic clearance of lignocaine was lower in the aged. Elimination half-life was longer in the elderly but there was no significant difference in apparent volume of distribution or systemic clearance of lignocaine. Plasma clearance of indocyanine green showed no correlation with systemic lignocaine clearance and was lower in the aged subjects. Blood/plasma lignocaine ratio was less than unity in both groups. Binding of lignocaine to plasma proteins showed concentration-dependence and was higher in the geriatric group. Maximum binding capacity of lignocaine was greater in the elderly but the binding affinity did not significantly change with age. Greater oral bioavailability of drugs like lignocaine may produce higher plasma concentrations in the elderly. Unlike indocyanine green, the systemic clearance of lignocaine was unaltered by age in this group of non-smokers. The protein-binding of lignocaine, like many other basic drugs, is increased in elderly subjects.
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  • 105
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    European journal of clinical pharmacology 29 (1985), S. 345-349 
    ISSN: 1432-1041
    Keywords: pefloxacin ; renal insufficiency ; pharmacokinetics ; haemodialysis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The kinetics of pefloxacin has been studied after a single intravenous infusion of 8 mg·kg−1 in 15 male patients with various degrees of renal failure. No difference in distribution or elimination of the drug was observed between patients with mild or severe renal impairment. The mean volume of distribution (Vd area) and the mean plasma clearance were 2.03l·kg−1 and 121.3 ml·min−1, respectively. The mean apparent elimination half-life was 13.5 h. These values are close to those observed in healthy subjects. No accumulation of the active N-desmethylmetabolite was observed in cases of severe failure as compared to mild impairment; its apparent elimination half-life was about twice that of the parent drug. The efficacy of a 4 h haemodialysis in 6 additional anuric subjects done to remove pefloxacin from the body was poor.
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  • 106
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    European journal of clinical pharmacology 29 (1985), S. 337-343 
    ISSN: 1432-1041
    Keywords: piretanide ; renal failure ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Piretanide 60 mg was administered intravenously over 30 min to 15 men with different degrees of renal failure. The mean piretanide serum concentration at the end of the infusion period was 5.72±1.51 µg/ml. Serum piretanide concentration-time curves declined biexponentially and 24 hours after medication the serum level had fallen to less than twice the detection limit. The terminal half-life ranged from 1.63 to 3.44 h. A relationship to creatinine clearance was not demonstrable. The mean metabolic clearance of piretanide was 107.7±47.6 ml/min/1.73 m2 body surface area and was the same as that reported for healthy subjects. The renal clearance of piretanide ranged from 3.33 to 43.9 ml/min/1.73 m2 body surface area and very closely correlated with the creatinine clearance (p〈0.01). Its renal clearance dependend principally on active secretion of the drug into the tubule, and glomerular filtration appeared unimportant. There was a close relationship between the amount of piretanide excreted in the urine and the creatinine clearance. Because the diuretic effect of piretanide depends on the concentration of the drug in the tubule, the observed correlation might be of use in evaluating the appropriate dosage of piretanide in patients with renal failure. The present data suggest that single daily doses of piretanide will not result in accumulation, even when high doses are administered to patients with advanced renal failure.
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  • 107
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    European journal of clinical pharmacology 28 (1985), S. 205-212 
    ISSN: 1432-1041
    Keywords: adriamycin ; cancer patients ; infusion ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The plasma pharmacokinetics of adriamycin has been studied in 21 cancer patients (31–85 years old) without liver tumours after short (3.00 min) and prolonged (45 min-16h) i.v. infusions. The area under the plasma concentration-time curve and the maximum plasma concentration compensated for dose variation showed a more than 3-fold individual variation. The pharmacokinetics of adriamycin was linear. There was no pharmacokinetic rational for variation of the dose with the age of the patients. There was good agreement between the measured plasma concentration-time curves for prolonged infusions and curves predicted from pharmacokinetic data from short term infusions.
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  • 108
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    European journal of clinical pharmacology 28 (1985), S. 333-337 
    ISSN: 1432-1041
    Keywords: cefotoxin ; renal failure ; peritoneal dialysis ; pharmacokinetics ; CAPD (continuous ambulatory dialysis) ; dialysate concentration ; intra peritoneal administration
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of cefoxitin was examined in 9 patients undergoing peritoneal dialysis for chronic renal failure. Cefoxitin was administered intraperitoneally in the dialysate fluid every 6 h for 24 h, in two different concentrations, 50 µg/ml and 100 µg/ml. The plasma half-life of cefoxitin was 20.2 h. The major route of elimination was non-renal, with a clearance of 8.0 ml/min. Peritoneal clearance was 4.1 ml/min. As expected, renal clearance was negligible. The peak plasma concentrations of cefoxitin at the two dose levels used were 7 µg/ml and 15 µg/ml, respectively, when assayed by HPLC, and 12 µg/ml and 24 µg/ml when determined by a microbiological assay. The cefoxitin concentration in the dialysate decreased from 50 µg/ml to 14 µg/ml and from 100µg/ml to 37 µg/ml during the 6 h of its retention in the peritoneal cavity.
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  • 109
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    European journal of clinical pharmacology 28 (1985), S. 317-320 
    ISSN: 1432-1041
    Keywords: bufuralol ; debrisoquine ; sparteine ; genetic/oxidative polymorphism ; metabolism ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Bufuralol is a beta-adrenoceptor blocking drug whose oxidative metabolism is under the same genetic control as debrisoquine and sparteine. The pharmacokinetics of bufuralol were studied in 10 healthy subjects (7 extensive and 3 poor metabolizers of debrisoquine) after oral and intravenous administration. In extensive metabolizers the systemic availability of bufuralol was 43%. Poor metabolizers were characterized by a considerable increase in systemic availability due to a corresponding decrease in hepatic first-pass metabolism. After oral administration of bufuralol non-linear kinetics may occur.
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  • 110
    ISSN: 1432-1041
    Keywords: prenalterol ; cardiac failure ; pharmacokinetics ; concentration-effect relationships
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Prenalterol was administered as an intravenous infusion at three incremental rates (60, 120 and 240 nmol/min) to five patients with severe cardiac failure. Haemodynamic, hormonal and metabolic variables were measured at the same time as plasma prenalterol concentrations, and the pharmacokinetics of the drug were studied by following plasma concentrations and urinary excretion during and after the infusion. Concentration-dependent increases in cardiac index, stroke index and stroke work index were observed without increases in arterial pressure, heart rate or myocardial oxygen demand. The reninangiotensin-aldosterone system was stimulated, although the extent of stimulation varied among patients. No strong correlations were found between the logarithm of the plasma prenalterol concentration and effect. Plasma clearance of the drug was lower in cardiac patients than in normal volunteers, but a large decrease in renal clearance was partially balanced by an increase in nonrenal clearance. Over the observed range of concentrations, no deviation from linearity was evident, and plasma concentrations of about 150 nmol/l were effective in improving cardiac function without significant side-effects.
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  • 111
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    European journal of clinical pharmacology 28 (1985), S. 405-410 
    ISSN: 1432-1041
    Keywords: verapamil ; renal failure ; norverapamil ; pharmacokinetics ; haemodialysis ; ECG ; blood pressure ; heart rate
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of verapamil was studied in patients with end-stage chronic renal failure and in normal subjects after i.v. injection of 3 mg and a single oral dose of 80 mg. Plasma levels of verapamil and its active metabolite norverapamil were measured by HPLC. After i.v. injection, the terminal phase half-life and total plasma clearance of verapamil in both groups were similar. Haemodialysis did not change the time course of plasma verapamil levels after i.v. administration. After a single oral dose, the plasma levels of verapamil and norverapamil in both groups of subjects were similar. Subsequently, normal volunteers and patients with renal failure were treated for 5 days with oral verapamil 80 mg t.d.s. There was no difference between the 2 groups of subjects in the trough and peak levels of verapamil or of norverapamil. Intravenous and oral administration of the calcium channel blocking agent had similar effects on blood pressure, heart rate and the PR-interval in the electrocardiogram in both groups. The study demonstrated that the disposition of verapamil was similar in normal subjects and in patients with renal failure.
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  • 112
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    European journal of clinical pharmacology 28 (1985), S. 411-417 
    ISSN: 1432-1041
    Keywords: ketanserin ; ketanserinol ; pharmacokinetics ; age ; healthy volunteers ; bioavailability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The bioavailability of ketanserin has been examined in a cross-over experiment in 21 elderly subjects (aged 59–72 years) by administration of tablets (40 mg), solution (40 mg) and injectable solution (10 mg). After two weeks of treatment with 40 mg ketanserin tablets further 18 blood samples for analysis were collected under steady-state conditions. Plasma levels were measured by HPLC. The absolute bioavailability of ketanserin tablets was 52.7%; their relative bioavailability compared to a solution containing an equal quantity of active compound was 85.5%. Therefore, the low absolute bioavailability of ketanserin cannot be attributed to the formulation. The active compound was rapidly liberated from the tablet, reaching a peak of 103.8 ng/ml after 0.97 h. Individual plasma level-time curves were fitted to an open three compartment model and a half-life of 17.7±7.26 h was calculated for the terminal elimination phase. An average terminal elimination half-life of 15.4±4.2 ng/ml was found after administration of the ketanserin solution. Multiple dosing with 40 mg tablets b.d.s. resulted in an AUC over one dosing interval at steady-state of 666±201 ng × h/ml. The AUC extrapolated to infinity was 1200±405 ng × h/ml for the last tablet. This is 1.8-times the AUC in one dosing interval, and 2.3-times the AUC of a single dose. Under steady-state conditions, the mean peak plasma level was 155.1 ng/ml (1.08 h after dosing) and the terminal half-life was 19.1±5.1 h. For the metabolite ketanserinol terminal half-lives of 21.4 h after a single tablet and 31.0 h after discontinuation of multiple dosing were calculated. Compared to the parent compound there was much more marked accumulation of ketanserinol. Despite moderate accumulation and prolongation of the terminal half-life of ketanserin under steady-state conditions, dosage adjustment is not required in elderly people. First-pass metabolism and bioavailability remained in the range found in previous studies of ketanserin in young subjects.
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  • 113
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    European journal of clinical pharmacology 28 (1985), S. 543-552 
    ISSN: 1432-1041
    Keywords: thiopentone ; anaesthesia ; intravenous anaesthesia ; multi-stage infusion ; exponential infusions ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Several multi-stage infusion regimens and a computer controlled exponentially decreasing infusion regimen were evaluated in twelve patients undergoing head and neck surgery or neurosurgery. Thiopentone dosage was based on the mean of pharmacokinetic parameter values from the literature and adjusted for each patient's lean body mass in order to rapidly achieve a predetermined plasma thiopentone concentration of 15 or 20 µg/ml in the period following the initial bolus dose to induce anaesthesia. Anaesthesia was satisfactory in all cases. Plasma thiopentone concentrations were maintained between 10–20 µg/ml during infusion in the five patients who received either a four or five stage infusion and in the six patients who received the exponential infusion, but not in the single patient who received a two-stage infusion. The mean recovery time was 111 min. The plasma concentrations of total and unbound thiopentone at awakening showed little intersubject variability, despite considerable differences in total dose and duration of infusion, suggesting the absence of acute tolerance to the drug. Plasma clearance of total thiopentone correlated strongly with calculated lean body mass and to a lesser extent with total body weight suggesting that lean body mass, in particular, should be an accurate predictor of thiopentone maintenance dose requirements. This study shows that it is feasible to use thiopentone as a primary anaesthetic agent during surgery by administering the drug either as an exponentially decreasing infusion or as an infusion comprising 4 or 5 stepwise decreasing rates.
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  • 114
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    European journal of clinical pharmacology 28 (1985), S. 585-588 
    ISSN: 1432-1041
    Keywords: isoxicam ; pharmacokinetics ; renal failure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The accumulation and disposition of the non-steroidal antiinflammatory drug isoxicam were investigated following its oral administration to 6 subjects with normal renal function and 13 patients with diminished renal function. Isoxicam was given daily as a single oral dose for 14–15 consecutive days. Steady-state plasma levels were achieved after 13 days. The effect of differences in renal function on the kinetics of isoxicam appeared to be minimal. Accumulation of isoxicam was similar in both groups of subjects and there was no significant difference between the groups in the plasma clearance or terminal half-life of isoxicam. There were substantial differences between individuals in the apparent plasma clearance and half-life of the drug, and this is reflected in the 7-fold range of steady-state plasma isoxicam concentrations encountered in the subjects.
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  • 115
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    European journal of clinical pharmacology 28 (1985), S. 611-613 
    ISSN: 1432-1041
    Keywords: molsidomine ; angina pectoris ; pharmacokinetics ; molsidomine retard
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Molsidomine (N-carboxy-3-morpholino-sydnonimine-ethylester; Cassella-Riedel Pharma GmbH, Frankfurt/M. FRG) has an antianginal effect for up to 3–5 h after oral administration of 2 mg Corvaton [1]. Plasma levels of the parent drug can be measured during this interval. A new galenic formulation (Corvaton retard) has been developed to prolong the duration of the therapeutic action and to improve patient compliance. The present study was carried out to establish whether the in vitro dissolution profile of the tablet was reflected in vivo, thus permitting prediction of plasma molsidomine levels in patients with coronary heart disease.
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  • 116
    ISSN: 1432-1041
    Keywords: omeprazole ; renal failure ; gastric secretion ; pharmacokinetics ; haemodialysis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The inhibitory effect of omeprazole on gastric acid secretion was tested in a group of patients on haemodialysis for chronic renal failure. Single 30 mg doses almost totally inhibited basal acid output on both dialysis and non-dialysis days. Plateau acid output was reduced by a mean of 77% and 90% on non-dialysis and dialysis days respectively. The absorption and pharmacokinetic profile of omeprazole were not affected by dialysis. Omeprazole was not recoverable from dialysis fluid. It is concluded that omeprazole is a potent inhibitor of gastric acid secretion in patients with chronic renal failure, and its effect is not influenced by haemodialysis.
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  • 117
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    European journal of clinical pharmacology 28 (1985), S. 659-664 
    ISSN: 1432-1041
    Keywords: BTS 49465 ; hypertension ; pharmacokinetics ; blood pressure effect ; heart rate effect ; side-effects ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetic and haemodynamic effects of a 200 mg oral dose of BTS 49465 (7-fluoro-1-methyl-3-methylsulphinyl-4-quinolone) were investigated in a double-blind placebo controlled study. BTS 49465 was rapidly absorbed and cleared from the systemic circulation with a half-life of 1.6 h by oxidation to the sulphone metabolite. The metabolite was cleared with a half-life of 37.6 h. Saliva concentrations of both BTS 49465 and its metabolite correlated well with the plasma concentrations. Compared to placebo, BTS 49465 produced statistically significant reductions in blood pressure and increases in heart rate both supine and after a 60° head up tilt. The time course of the haemodynamic changes suggested that the sulphone metabolite contributed to the overall hypotensive response. Plasma Renin Activity was only marginally elevated and there was no evidence of acute fluid retention. BTS 49465 was well tolerated in terms of haematological and biochemical parameters and subjective side-effects.
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  • 118
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    European journal of clinical pharmacology 28 (1985), S. 665-670 
    ISSN: 1432-1041
    Keywords: tocainide ; renal failure ; pharmacokinetics ; oral dosing ; pharmacodynamics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The plasma levels of tocainide have been followed after oral administration of 600 mg p.o. to 20 patients with renal failure due to various causes, and to 8 healthy controls. The peak plasma concentrations in the patients with pyelonephritis (3.80 µg/ml) and interstitial nephritis (3.74 µg/ml) but not in those with glomerulonephritis (3.17 µg/ml) differed from that in healthy volunteers (3.24 µg/ml). The renal clearance of tocainide was well correlated with the endogenous creatinine clearance and was dependent on urine pH. No difference in renal clearance was observed between the patients groups. It is suggested that the changes in plasma levels are a consequence of decreased renal clearance. Creatinine clearance was shown to be a poor estimator of tocainide clearance, which suggests that extrarenal clearance plays an important role in the handling of the drug in the body. The findings are used to suggest a safe dosage regimen.
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  • 119
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    European journal of clinical pharmacology 28 (1985), S. 721-722 
    ISSN: 1432-1041
    Keywords: chloroquine ; rheumatoid disease ; desethylchloroquine ; capacity limitation ; pharmacokinetics ; metabolism
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The kinetics of chloroquine and its major metabolite desethylchloroquine were studied in patients with rheumatoid disease after single oral doses of chloroquine phosphate corresponding to 150 and 300 mg chloroquine base. The findings strengthen the previous finding that the disposition of chloroquine involves rate limiting steps.
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  • 120
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    European journal of clinical pharmacology 28 (1985), S. 689-692 
    ISSN: 1432-1041
    Keywords: isoxicam ; piroxicam ; pharmacokinetics ; elderly ; anti-inflammatory drugs
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of isoxicam and piroxicam were compared in 12 young adults (〈40 years) and 12 elderly subjects (〉65 years). After a single oral dose of 200 mg isoxicam or 20 mg piroxicam blood samples were taken for 168 h and the plasma drug concentrations determined by HPLC. The elimination half life of piroxicam for the adults was 57.1±16.4 h (mean ± SD; harmonic mean 52.9 h) and for the elderly subjects was 57.8±22.1 h (harmonic mean 52.1 h). The corresponding values after isoxicam were 34.3±13.6 h (harmonic mean 31.6) for the adults and 39.1±22.7 h (harmonic mean 33.5) for the elderly subjects. Similarly no differences were noted in either the AUC0-∞ after piroxicam (adults 154.1±52.2 µg·h/ml, elderly 163.6±99.1 µg·h/ml) and isoxicam (adults 642.7±241.9 µg·h/ml, elderly 787.9±613.1 µg·h/ml) or the apparent oral clearance of piroxicam (adults 2.39±0.80 ml/min, elderly 2.51±0.90 ml/min) and isoxicam (adults 5.84±2.04 ml/min, elderly 5.59±2.12 ml/min). One adult and two elderly subjects exhibited slower elimination of both medicines than the remainder of each group. However determination of the oxidation phenotype using sparteine metabolism showed that this was not a likely determinant of the reduced clearance.
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  • 121
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    European journal of clinical pharmacology 28 (1985), S. 77-84 
    ISSN: 1432-1041
    Keywords: β-Blockers ; debrisoquine metabolism ; extensive metabolizers ; genetic polymorphism ; poor metabolizers ; glucuronidation ; lipophilicity ; pharmacodynamics ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Although β-Blockers are structurally closely related, there are marked differences in the extent of metabolism, related mainly to relative lipophilicity. Lipophilic β-Blockers are metabolized by C-oxidative pathways and glucuronidation. Metabolism of lipophilic β-Blockers is important in determining pharmacokinetics, formation of active metabolites, stereoselectivity and isomer preference, and interphenotypic variation. The oxidative clearance of metoprolol, timolol and bufuralol is regulated/influenced by the debrisoquine hydroxylation gene locus. The metabolism of these lipophilic β-Blockers thus exhibits polymorphic characteristics, there being significant interphenotype differences in pharmacokinetics (bioavailability, peak plasma level, plasma terminal t1/2) between the poor and extensive metabolizers of debrisoquine. There are similar interphenotype differences in β-blocker pharmacodynamics in terms of β-blockade. A number of adverse effects of lipophilic β-Blockers have been hypothesized to predominate in the poor metabolizer phenotype including unacceptable bradycardia, loss of cardioselectivity, greater CNS side-effects, and interactions with drugs metabolized by the same polymorphic systems. However, objective evidence for this is lacking.
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  • 122
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    European journal of clinical pharmacology 29 (1985), S. 461-465 
    ISSN: 1432-1041
    Keywords: carteolol ; chronic renal failure ; pharmacokinetics ; dosage adjustment ; metabolism
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The plasma levels and urinary excretion of carteolol and its main metabolites 8-hydroxycarteolol and carteolol glucuronide were investigated in 6 healthy subjects and 9 patients with varying degrees of renal impairment following a single oral dose of 30 mg carteolol hydrochloride. In healthy subjects the half-life of carteolol was 7.1 h. 63% of the administered dose was recovered unchanged in urine, and in all 84% was excreted by the kidneys. The renal clearance of carteolol was 255 ml/min. In chronic renal failure (CRF) the terminal half-life was increased to a maximum of 41 h. Both the elimination rate constant and renal clearance were closely related to the creatinine clearance. In CRF the recovery of carteolol and its metabolites from urine was considerably reduced, suggesting that another pathway of drug elimination becomes relevant in renal disease. To avoid an increase in side-effects due to drug accumulation, the dosage of carteolol should be adjusted in relation to the reduction in creatinine clearance. The maintenance dose should be reduced to a half in patients with a creatinine clearance below 40 ml/min and above 10 ml/min. In those with a creatinine clearance of 10 ml/min or less, the dose should be reduced to 1/4.
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  • 123
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    European journal of clinical pharmacology 29 (1985), S. 477-481 
    ISSN: 1432-1041
    Keywords: budesonide ; glucocorticoid ; nasal administration ; pharmacokinetics ; bioavailability ; systemic effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Budesonide, a topically potent glucocorticoid, was administered to 4 healthy volunteers by i.v. infusion and by nasal instillation of 100 µg tritium-labelled drug. Plasma was analyzed by liquid chromatography plus scintillation counting of collected fractions. After i.v. administration the plasma clearance was 0.92 l/min and the apparent volume of distribution was 2.8 l/kg. After nasal administration, the time to reach the peak plasma level was approximately 30 min, and the systemic availability was 102%. Budesonide had marginal effects on plasma cortisol and white blood cell counts either after i.v. or nasal administration. Thus, nasally instilled budesonide in solution is rapidly and completely absorbed from the nasal mucosa. The systemic effects after this clinically recommended nasal dose were negligible.
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  • 124
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    European journal of clinical pharmacology 28 (1985), S. 197-204 
    ISSN: 1432-1041
    Keywords: triprolidine ; BW 825C ; pharmacokinetics ; pharmacodynamics ; sedation ; intradermal histamine ; human performance
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The new H1-receptor antagonist BW 825C and triprolidine (2.5 and 5 mg) were administered to 12 healthy male volunteers in a double blind placebo controlled, balanced, crossover design. Histamine antagonism was measured by assessment of flare and weal areas after intradermal injection of histamine. The 2 compounds were approximately equipotent in blocking the flare and weal response to intradermal histamine and had a similar duration of action. Triprolidine impaired performance of vigilance and reaction time (p〈0.05) compared with placebo while BW 825C did not. Drowsiness measured using visual analogue scales followed both triprolidine treatments, but not BW 825C. BW825C had a plasma half-life (t1/2) of 1.7±0.2 h and triprolidine of 4.6±4.3 h. The peak plasma level of BW 825C was approximately 6 times that of triprolidine. It was concluded that BW 825C might be a clinically active H1-antagonist with reduced sedative side-effects.
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  • 125
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    European journal of clinical pharmacology 28 (1985), S. 225-227 
    ISSN: 1432-1041
    Keywords: theophylline ; absorption ; food intake ; aqueous solution ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effect of food on the rate and extent of absorption of theophylline was studied in healthy adults given a single dose of theophylline (aqueous solution of choline theophyllinate containing 270 mg of theophylline) in the evening either on an empty stomach or together with supper. Food appeared to decrease the absorption rate of theophylline significantly, tmax being prolonged from 1.34 h (mean) to 4.40 h and cmax decreased from 7.82 mg·l−1 to 5.47 mg·l−1. The area under the plasma concentration-time curve (AUC) after drug intake with supper was slightly but not significantly smaller, indicating that theophylline (as a solution of choline theophyllinate) can be taken together with food without substantial loss of the quantity of drug absorbed. The elimination rate was not influenced by concomitant intake of supper.
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  • 126
    ISSN: 1432-1041
    Keywords: amiodarone ; warfarin ; drug interaction ; metabolism ; inhibition ; plasma concentration ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Potentiation of the anticoagulant-effect of warfarin by amiodarone was studied in 30 patients. Thirteen received both drugs concurrently, and 17 received warfarin alone and the combination sequentially. Warfarin doses were adjusted to maintain the prothrombin time between 25–30% of control and its kinetics were compared to those in 20 control patients who received warfarin alone. Potentiation occurred in 28/30 patients, presenting as a 35%–65% reduction in the required dose of warfarin, and was correlated with the dose of amiodarone (r=0.77, p〈0.01). The free warfarin fraction was not affected by amiodarone (1.8% vs 1.6% in the controls). Warfarin clearance was lower in amiodarone-treated patients than in the controls (1.4 vs 3.1 ml/min, p〈0.01) with similar plasma concentrations (1.5 vs 1.2 µg/ml) despite administration of lower doses (23.3 vs 39 mg/week respectively). The amiodarone concentration was significantly correlated with the warfarin concentrations independent of the effect of amiodarone on the dose of warfarin. Amiodarone hat no effect on prothrombin other than through its actions on the dose and plasma concentration of warfarin. The mechanism of the amiodarone-warfarin interaction is pharmacokinetic through dose — and concentration — dependent inhibition of warfarin elimination.
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  • 127
    ISSN: 1432-1041
    Keywords: famotidine ; renal failure ; H2-receptor antagonist ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of a new, potent H2-receptor antagonist, famotidine, 20 mg i.v. was studied in 7 subjects with normal renal function and in 24 patients with varying degrees of renal impairment. The volume of distribution at steady state was 1.14 l/kg in normal subjects and was not altered in renal failure. The half-life of elimination was 2.59 h in normal subjects and was unchanged in mild renal failure (creatinine clearance, CLCR 90–60 ml/min/1.48 m2) but was increased to 4.72 h in moderate renal failure (CLCR 60–30 ml/min/1.48 m2), and to 12.07 h in severe renal failure (CLCR below 30 ml/min/1.48 m2). The cumulative urinary excretion and renal clearance of famotidine were correspondingly reduced in patients with impaired kidney function. In normal subjects and in patients with mild to moderate renal failure, about 70% of famotidine was excreted through the kidney, mainly by tubular secretion. In patients with a CLCR above 60 ml/min/1.48 m2 the normal daily dose of famotidine can be employed, but in those with a CLCR between 60 and 30 ml/min/1.48 m2 the dose should be reduced by half, and in patients with a CLCR below 30 ml/min/1.48 m2 a reduction by three quarters of the normal dose is recommended.
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  • 128
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    European journal of clinical pharmacology 28 (1985), S. 425-428 
    ISSN: 1432-1041
    Keywords: caffeine ; oral contraceptives ; pharmacokinetics ; elimination half-life
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effect of chronic (〉3 months) administration of low-dose oestrogen-containing (〈50 µg oestrogen) oral contraceptives (OCS) on the pharmacokinetics of caffeine has been examined in a treated females matched with 9 non-smoking, drug-free, healthy control females of similar age, weight and ethnic origin. Each subject received 162 mg caffeine base orally after an overnight fast. OCS subjects had a prolonged elimination half-life of caffeine, (mean 7.88 h vs 5.37 h in the controls). This was the result of marked impairment of the plasma clearance of caffeine (1.05 vs 1.75 ml/min/kg, respectively) with no change in apparent volume of distribution (0.685 in OCS vs 0.750 l/kg in the control group). The absorption parameters determined were peak plasma caffeine concentration (3.99 vs 4.09 µg/ml) and time to peak concentration after drug administration (1.52 vs 0.79), which was moderately prolonged in OCS users. Thus, caffeine clearance, previously reported to be a specific marker of cytochrome P-448 activity in man, is decreased by chronic OCS use. This suggests that OCS may cause significant impairment of this enzyme activity as assessed in vivo. With chronic caffeine consumption, OCS users are predicted to have an increased steady-state plasma caffeine concentration as compared to non-OCS users.
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  • 129
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    European journal of clinical pharmacology 28 (1985), S. 433-437 
    ISSN: 1432-1041
    Keywords: isofezolac ; probenecid ; pharmacokinetics ; anti-inflammatory drug ; drug interaction ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The interaction between isofezolac and probenecid has been studied with the aid of a specific HPLC assay for isofezolac in plasma and urine. 8 healthy adult volunteers received a single 40 mg oral dose of isofezolac before and after 3 days of loading with 0.5 g probenecid t.i.d. There was an increase in the maximum plasma isofezolac concentration from 2.44 to 3.38 µg · ml−1 when probenecid was given. The AUC of isofezolac in plasma increased from 6.73 to 11.28 µg · h · ml−1. After the last dose in a 7 day treatment with 40 mg isofezolac t.i.d., there was an increase in the maximum plasma isofezolac level from 2.84 to 4.96 µg · ml−1 when probenecid was given. The rate of absorption of isofezolac was not affected. An increase in the AUC of isofezolac in plasma was observed from 11.74 to 26.34 µg · h · ml−1. The major effect of probenecid on isofezolac metabolism was a 50% reduction in total isofezolac (free+conjugates) excreted inurine. Because of this interaction, patients given isofezolac combined with probenecid will have a higher steady-state plasma level of isofezolac than when probenecid is not administered.
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  • 130
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    European journal of clinical pharmacology 28 (1985), S. 453-456 
    ISSN: 1432-1041
    Keywords: zimeldine ; norzimelidine ; pharmacokinetics ; renal insufficiency
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The kinetics of zimeldine (Z) and its demethylated metabolite, norzimelidine (NZ), were determined after administration of a single 200 mg oral dose of Z to 6 healthy volunteers (Group I), and to patients with mild (Group II) and severe renal failure (Group III). Z and NZ concentrations were assayed by HPLC in serial plasma and urine samples over 6 days following the dose. In Group I Z was rapidly absorbed and metabolized into NZ, and then the plasma concentrations declined with apparent elimination half-lives of 8.4 h and 24.9 h for Z and NZ respectively, whilst the renal clearance of both compounds was low, Z 15.7 ml/min and NZ 33.0 ml/min. The plasma level of Z differed little between Groups I and III, but the area under the curve was significantly higher in Group III than in Group I subjects (AUC0–144=17.3 and 6.8 µmol·l−1·h, respectively). Severe renal failure did not affect the peak plasma concentration of NZ but it did significantly increase peak time, apparent elimination half-life, and the area under the plasma concentration curve. A significant inverse relationship was found between renal clearance of NZ and plasma creatinine. Since NZ is as pharmacologically potent as Z, the results suggest that the dose of Z should be reduced in patients with severe renal insufficiency.
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  • 131
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    European journal of clinical pharmacology 28 (1985), S. 429-431 
    ISSN: 1432-1041
    Keywords: theophylline ; asthma ; personality measures ; pharmacokinetics ; volunteers ; patients
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Thirteen volunteers received an iv dose of theophylline followed by blood sampling for 8 h to calculate pharmacokinetic parameters. Ten patients with asthma undergoing chronic dosing with slow release aminophylline underwent 12 h of blood sampling to calculate theophylline clearance. Both groups completed an Eysenck Personality Inventory (EPI) from which was derived scores for neuroticism (N) and extroversion (E). Using multiple regression analysis no independent effect of either N or E score on theophylline clearance or half-life could be demonstrated.
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  • 132
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    European journal of clinical pharmacology 28 (1985), S. 439-445 
    ISSN: 1432-1041
    Keywords: acetohydroxamic acid ; staghorn renal calculi ; pharmacokinetics ; 14C-labeled drug ; acetamide
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Acetohydroxamic acid (AHA), a bacterial urease inhibitor, has been recently approved by the United States Food and Drug Administration as a potential drug for the successful treatment of patients with infection induced staghorn renal calculi. The present study was designed to evaluate the disposition of 14C-AHA following oral administration to patients. The results of the study, while in a limited number of patients, indicate that upon oral administration, AHA is very rapidly absorbed from the gastrointestinal tract. Evaluation of urinary excretion data suggests that patients with compromised renal function have low recoveries of AHA in the urine. These data are supported by a strong linear correlation between creatinine clearance and AHA elimination. Acetamide and CO2 are identified as the two major metabolites of AHA in man. CO2 is eliminated in the breath and accounts for 20–45% of the administered dose, while acetamide is eliminated in the urine and accounts for only 9–14% of the administered dose. The remaining dose is eliminated as intact AHA in the urine (19–48%). Saliva concentrations of total radioactivity depict a strong positive correlation with their respective plasma concentrations. Parameter estimates from 14CO2 concentrations in breath as a function of time data closely correspond to the pharmacokinetic parameters of AHA in patients indicating that CO2 may be a primary metabolite derived directly from AHA rather than a secondary metabolite formed by the metabolism of an intermediate product. Upon multiple dose administration of AHA, there is the potential for significant accumulation of acetamide due to its relatively long half-life.
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  • 133
    ISSN: 1432-1041
    Keywords: methotrexate ; osteosarcoma ; high parenteral dose ; pharmacokinetics ; drug monitoring ; computer prediction
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Methotrexate (MTX) in serum was measured by RIA in 12 cancer patients receiving high doses of MTX (2 to 8 g/m2) in 6 hour infusions 69 treatments were studied. The peak serum level was proportional to the dose administered and was always greater than 10−4 M. 2 elimination phases were seen: the first had a mean half-life of 2.36 h and the second a mean half-life of 16.14 h. 24 hours after beginning the infusions there were very large variations in individual serum concentrations of MTX, from 2.4 10−6 M to 1.9 10−5 M by 24 h after 8 g/m2. To control these variations, a mathematical model for prediction of the individual pharmacokinetic pattern of a 6 hour-infusion of high-dose MTX by kinetic analysis of a low-test dose is proposed. A program was created for an Apple III computer using toxic and therapeutic serum levels of MTX selected by the clinician. The computer program is adaptable to any infused substance for variable infusion times, thus introducing new advances over existing methods.
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  • 134
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    European journal of clinical pharmacology 28 (1985), S. 581-583 
    ISSN: 1432-1041
    Keywords: piretanide ; liver cirrhosis ; ascites ; bioavailability ; pharmacokinetics ; diuretic
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of piretanide, a new loop diuretic, were studied in seven patients with severe liver disease before and after resolution of ascites. The time to maximum concentration was significantly prolonged by the presence of ascites. Tmax after relief of ascites was similar to that seen for normal volunteers. Area under the curves, bioavailability, volumes of distribution and elimination half-lives did not change after resolution of the ascites: two patients in whom diuretic resistant ascites occurred showed similar pharmacokinetics to that of the diuretic responders. Reduced responsiveness to piretanide therapy in patients with gross ascites does not appear to be the result of decreased bioavailability.
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  • 135
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    European journal of clinical pharmacology 28 (1985), S. 641-647 
    ISSN: 1432-1041
    Keywords: Femoxetine ; alcohol interaction ; psychomotor performance ; pharmacokinetics ; amitriptyline ; plasma 5HT
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effects on human psychomotor performance of femoxetine (FEMO), a 5-hydroxytryptamine-selective antidepressant, alone and in combination with alcohol (EtOH) were compared with those of amitriptyline (AMI) and placebo in a controlled double-blind crossover trial in 11 student volunteers. Objective measurements (body sway, choice reaction, flicker fusion, tracking, nystagmus, digit symbol substitution, backwards recall) and subjective self-assessment (visual analogue scales, reporting of side-effects) were done after single doses of FEMO, AMI and placebo, and subacute administration of FEMO and placebo. Single doses of 200 mg FEMO did not impair psychomotor performance, but 50 mg AMI did so in several respects. AMI but not FEMO increased the objective and subjective effects of EtOH. After FEMO 600 mg/d for 10 days almost no objective difference from placebo was noted, although mild sedation at home was reported as a side-effect. FEMO either did not increase or slightly decreased the effect of EtOH on reactive and co-ordination skills. The plasma concentrations of FEMO varied widely from 0 to 156 ng/ml, as in previous clinical trials but reduced a blood 5-hydroxytryptamine concentration in each subject indicating an effect of FEMO on serotoninergic mechanisms.
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  • 136
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    European journal of clinical pharmacology 28 (1985), S. 45-51 
    ISSN: 1432-1041
    Keywords: disopyramide ; myocardial infarction ; antiarrhythmic agent ; pharmacokinetics ; protein binding ; intravenous administration ; oral administration ; gastro-intestinal absorption
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary To study the effects of acute myocardial infarction on the pharmacokinetics of disopyramide a single oral dose of disopyramide base (200 mg) was administered to 6 patients with myocardial infarction both in the acute (Study I) and recovery (Study II) phases. An intravenous tracer dose of14C-disopyramide (2.5 µg/0.3 mg) was given simultaneously with the oral dose. On the basis of the intravenous tracer data, the volume of distribution, binding to plasma proteins, total plasma clearance, renal clearance and elimination half-life of disopyramide and mono-N-dealkyl disopyramide were the same in Studies I and II. The peak serum concentrations of disopyramide after oral dosing in Studies I and II were 2.6±1.2 (SEM) and 6.4±1.9 µg/ml, respectively (p〈0.05), the peak times 3.29±1.22 and 1.21±0.39 h (N.S.) and the AUCINF 38.0±7.7 and 60.7±9.9 µg·h·ml−1 (p〈0.05). The recovery of disopyramide in urine over 3 days averaged 46% and 47% of dose, and that of mono-N-dealkyl disopyramide 22% and 16% of the dose, respectively. Thus, the gastrointestinal absorption of disopyramide was disturbed, resulting in low plasma concentrations after oral dosing, whereas the elimination of disopyramide was unaltered in the acute phase of myocardial infarction.
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  • 137
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    European journal of clinical pharmacology 28 (1985), S. 41-43 
    ISSN: 1432-1041
    Keywords: disopyramide ; atenolol ; pharmacokinetics ; drug interaction ; ischaemic heart disease
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effect of atenolol on the total elimination of disopyramide and its main dealkylated metabolite was studied in 6 patients and 3 volunteers. During administration of 50 mg atenolol b.i.d. the clearance of disopyramide decreased significantly (p〈0.02) from 1.90±0.71 (X±SD) to 1.59±0.68 ml/kg/min, while its half-life, concentration of the metabolite, and the volume of distribution remained unchanged. The reduction in the clearance of disopyramide by atenolol might contribute to the alleged pharmacodynamic interaction between disopyramide and β-blocking drugs.
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  • 138
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    European journal of clinical pharmacology 28 (1985), S. 73-78 
    ISSN: 1432-1041
    Keywords: procyclidine ; Kemadrin ; pharmacokinetics ; pharmacodynamics ; humans
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics and pharmacodynamics of procyclidine (10 mg) after oral and intravenous administration were studied in six healthy volunteers. Treatment order was randomised and the study was placebo-controlled and conducted blind. After oral dosing the mean peak plasma concentration was 116 ng/ml and mean bioavailability was 75%. After both oral and intravenous dosing the mean values for the volume of distribution, total body clearance and plasma elimination half-life of procyclidine were in the order of 1 l/kg, 68 ml/min and 12 h respectively. Autonomic effects were maximal within 0.5 h of intravenous administration and at about 1–2 h after oral dosing. Significant effects on pupil diameter, visual near point, salivary secretion and heart rate occurred after intravenous treatment and similar but less marked effects occurred after the oral dose. Significant autonomic effects were still detectable 12 h after both forms of treatment.
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  • 139
    ISSN: 1432-1041
    Keywords: moclobemide ; Ro 11-1163 ; pharmacokinetics ; bioavailability ; MAO activity in platelets ; monoamine metabolites in urine ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The plasma concentrations of the MAO-inhibitor moclobemide (Ro 11-1163) were determined in six healthy male subjects after oral (tablets) administration. Effects on MAO activity in platelets and excretion of monoamine metabolites in urine were investigated. The design of the study was a double-blind cross-over study with single oral doses of placebo, 50, 100 and 200 mg of moclobemide. The elimination profile of the drug showed that the half life of the unchanged drug ranged between 1 and 2 h except in one subject with a half-life of about 4 h. The mean bioavailability calculated using flow model concepts was F=0.43 after 50 mg, F=0.47 after 100 mg and F=0.59 after 200 mg. The outlier with a t1/2 of 4 h was found to have a bioavailability of more than 0.80 after all 3 doses. The slightly increasing bioavailability with higher doses was interpreted as evidence of saturable hepatic first-pass elimination of the drug. MAO activity in platelets was measured before and 2, 6 and 24 h after drug administration. No inhibition of platelet MAO was obtained at any point in time or dose level, as to be expected since moclobemide preferentially inhibits MAO A. Urine excretion of the monoamine metabolites homovanillic acid (HVA), dihydroxyphenylacetic acid (DOPAC), 3-methoxy-4-hydroxy-phenylglycol (MOPEG) and 5-hydroxyindoleacetic acid (5-HIAA) was followed during 48 h after placebo, 50 and 200 mg of moclobemide. Time but not dose contributed significantly to the variability in excretion of the monoamine metabolites. An apparent reduction of HVA and DOPAC levels was obtained in the early phase after the administration of 200 mg of moclobemide. In 1 subject with a mild drug reaction a pronounced decrease in the levels of all the metabolites was obtained. In the other 5 subjects, the compound was very well tolerated with a few reported side-effects like increased activity, somnolence or sweatings. There was a slight but significant increase in blood pressure following 50 and 100 mg but not 200 mg of moclobemide.
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  • 140
    ISSN: 1432-1041
    Keywords: sulphinpyrazone ; metabolism ; single dose ; chronic treatment ; pharmacokinetics ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of sulphinpyrazone and its major metabolites (sulfide, sulfone, p-hydroxysulfone and p-hydroxy-sulphinpyrazone) were investigated in 9 volunteers after a single oral dose as well as after chronic treatment for 23 days. Chronic administration of sulphinpyrazone, in comparison with a single oral dose, led to significant changes in plasma AUC (115.86 to 42.90 mg/l·h), in renal clearance (1.06 to 1.80l/h), in hepatic intrinsic clearance (319.0 to 598.0l/h), and in the unbound fraction in plasma 1.15 to 1.69%) and in tissue (2.73 to 1.31%). The volume of distribution changed from 20.24 to 52.041. The steady state concentrations predicted from the single dose were significantly higher than the values found after chronic treatment. The results suggest that sulphinpyrazone induces its own metabolism. The metabolism of the sulfone, p-hydroxysulfone and the p-hydroxy-sulphinpyrazone to further degradation products was also induced. Chronic treatment with sulphinpyrazone reduced the plasma AUC of the sulfide and caused a decrease in its elimination half-life (20.9 to 14.3 h). Since considerable amounts of the sulfide are formed in the G.I. tract, it is suggested that besides the induction of metabolism, bacteria which reduce sulphinpyrazone to the sulfide may also be responsible for the observed pharmacokinetic changes.
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  • 141
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    European journal of clinical pharmacology 29 (1985), S. 503-509 
    ISSN: 1432-1041
    Keywords: deconvolution ; haemodialysis ; cefsulodin ; extracorporal drug removal ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary A novel approach to the evaluation of the kinetics of drug removal by an extracorporal device (ECD), e.g., haemodialysis, haemofiltration, and haemoperfusion, is presented. The rate and extent of extracorporal drug removal (ECR) are determined by deconvolution. The proposed method is model independent in the sense that no specific models of corporal or extracorporal disposition are required. The estimation of various derived functions and parameters useful for describing ECR such as clearance and fractional drug removal are facilitated by the technique. The kinetics of cefsulodin elimination by haemodialysis in 3 patients were evaluated using the deconvolution approach. The results indicated that cefsulodin was dialyzable with ∼50% of the drug in the body removed by haemodialysis over 3–4 h.
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  • 142
    ISSN: 1432-0738
    Keywords: Mercury ; Metallothionein ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The influence of the administered mass on the tissue and sub-cellular distribution of mercury (Hg) was investigated in rats, using 203Hg. The fraction of the dose deposited in liver increased threefold over the dose range 0.17–1.65 mg Hg · kg−1, while the retention in the kidney decreased by a factor of 2. The uptake in other organs, lung, spleen, brain, thymus, salivary glands showed no dose-dependent variation. Subcellular fractionation studies showed a dose-dependent increase in the Hg content of the liver cytosol, with corresponding decreases in the deposition in the lysosomal and nuclei-cell debris fractions. In contrast, no clear changes in the distribution of Hg amongst the subcellular organelles of the kidney were observed. The amount of Hg bound to metallothionein in the liver cytosol rose steeply with increasing dose. However, in the kidney cytosol the mass of Hg bound to metallothionein increased with dose up to 0.55 mg Hg · kg−1, thereafter remaining approximately constant. These observations suggest that the Hg-binding metallothionein in the kidney was saturated by administered doses greater than 0.55 mg Hg · kg−1, whereas in liver saturation levels of the metal were not reached even at the highest dose tested, 1.65 mg Hg · kg−1.
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  • 143
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    Archives of toxicology 56 (1985), S. 252-255 
    ISSN: 1432-0738
    Keywords: Cadmium ; Selenium ; Liver ; Kidney ; Rat ; Metallothionein
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract In acute studies, approximately 70–90% of cytosolic cadmium in liver and kidney has been shown to be bound to metallothionein, a low-molecular weight protein. In this study, we report on the influence of dietary selenium on the distribution of cadmium in rat kidney and liver. Contrary to the findings of most acute studies, our results indicate that only a relatively small proportion of cadmium (approximately 14% in the kidney and 44% in the liver) is bound to metallothionein when cadmium is administered for 7 weeks in the diet and via osmotic minipumps to selenium-deficient rats. Feeding rats the same diet supplemented with 1.0 ppm selenium results in no detectable cadmium-metallothionein peak in the kidney, and only about 10% of the cytosolic cadmium elutes as cadmium bound to metallothionein in the liver. In animals fed the selenium-supplemented diet, the bulk of the cadmium is recovered in the low-molecular weight fraction. Dietary selenium did not significantly affect the distribution of zinc and copper in the kidney or liver.
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  • 144
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    Archives of toxicology 56 (1985), S. 204-206 
    ISSN: 1432-0738
    Keywords: Peripheral neuropathy ; 2,5-hexanedione ; Conduction velocity ; Distal latency ; Vitamin B12 ; Vitamin B6 ; Therapeutic effects ; Rat ; Tail nerve
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The therapeutic effect of Vitamin B12 or Vitamin B6 on 2,5-hexanedione induced-neuropathy in animals was examined by using our electrodiagnostic technique in order to investigate the mechanism of the development of the neuropathy. Pyridoxal phosphate and two forms of Vitamin B12 were administered to rats intoxicated by the neurotoxin for a period of 18 weeks, and the sensory and motor fiber conduction velocity and the motor distal latency of the tail nerve were periodically determined. None of the groups treated with the therapeutic drugs exhibited a definite improvement in the nerve fiber conduction velocity and motor distal latency of the rat tail nerve, as compared with those of the 2,5-hexane-dione-treated controls.
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  • 145
    ISSN: 1432-0738
    Keywords: Thiabendazole ; Adenosine triphosphate ; Teratogenesis ; Mouse ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Ogata et al. (1984) reported that thiabendazole (TBZ) was teratogenic in mice when olive oil was used as a vehicle, but not teratogenic when administered in gum arabic. Results of investigations into the possible association between TBZ-induced teratogenicity and adenosine triphosphate (ATP) are reported here. ATP levels in the limb buds were measured at day 10 of gestation in controls and mice treated with 1300 mg/kg TBZ 24 h previously. The results showed that there was a correlation between the dosage of TBZ and the ATP levels of fore and hind limb buds (r=−0.827 and r=−0.799, respectively). ATP levels in mouse limbs were reduced to 22–31% of control values when TBZ was given in olive oil, but the ATP reduction was only 6–9% when TBZ was given in gum arabic. This suggests that there may be a relationship between the teratogenic and ATP-depressing action of TBZ on the limb buds of mouse embryos. Pregnant rats were also treated with TBZ. TBZ at a dose level of 1000 mg/kg was given orally on day 11 of gestation. After 24 h, ATP levels in fetal rat limbs were still 82% of control values. These results confirm the observations of Ogata et al. on the vehicle effect and the difference in response between mice and rats.
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  • 146
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    Archives of toxicology 56 (1985), S. 236-241 
    ISSN: 1432-0738
    Keywords: Methylmercury ; RNA synthesis ; Dorsal root ganglion ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The effect of methylmercury in vivo on the incorporation of 3H-uridine in vitro into RNA of dorsal root ganglia of the rat was examined. Modified methods for the incubation of the tissue and extraction of RNA were applied to adequately determine the rate of RNA synthesis. Methylmercury significantly decreased the RNA content and RNA synthetic activity only in the symptomatic period, while uptake of the precursor into the acid-soluble pool remained unchanged. These results indicate that the previously reported inhibition of protein synthesis in dorsal root ganglia at an early phase of methylmercury intoxication was not due to impairment RNA synthesis in this tissue.
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  • 147
    ISSN: 1432-0738
    Keywords: Oral cadmium ; Placenta ; Foetal organs ; Zn, Cu, Fe content ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Cadmium chloride was administered in drinking water at a concentration of 50 ppm cadmium to female rats for 20 days of gestation. The foetuses were then removed from the uteri of the dams. Gestational exposure to oral cadmium resulted in decreased zinc, copper, iron, metallothionein, and thionein-bound zinc content in foetal liver as well as in reduced copper content in placenta and foetal intestine, brain and kidney. Subcellular fractionation of the foetal liver revealed decreased nuclear and cytoplasmic zinc content as well as decreased microsomal iron content. Pregnant rats exposed to oral cadmium revealed decreased serum zinc and iron concentration as well as reduced ceruloplasmin activity. The decreased zinc, copper, and iron content in foetal organs is suggested to be causally connected with the diminished availability of these metals in the maternal circulation.
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  • 148
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    Archives of toxicology 56 (1985), S. 279-282 
    ISSN: 1432-0738
    Keywords: Hypothalamus ; Hypothermia ; Rat ; Thermogenesis ; Tributyl phosphorotrithioate
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Tributyl S,S,S-phosphorotrithioate (DEF) produces profound hypothermia in rats, mice and guinea pigs by inhibition of thermogenesis. Its actions on heat conservation and motor control are, however, minimal. It is effective against both shivering and non-shivering thermogenesis and completely blocks the increase in body temperature evoked by anterior hypothalamic stimulation. A number of other measures indicated that this is unlikely to be due to a lack of peripheral thermogenic capacity: thus plasma concentrations of glucose, free fatty acids, and ketone bodies remained normal or rose after DEF, and in vitro noradrenaline-stimulated lipolysis was normal in the presence of DEF. The metabolic response to the uncoupler, 2,4-dinitrophenol was unchanged by DEF, and the increase in temperature of brown fat evoked in vivo by nerve stimulation or noradrenaline was also unaffected. It is suggested that DEF (or more likely a DEF metabolite) acts selectively on a central thermogenic control process.
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  • 149
    ISSN: 1432-0738
    Keywords: 2,4,6-Trinitrotoluene ; Carcinogens ; 2,4-Dinitrotoluene ; Rat ; Mouse
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract 2,4,6-Trinitrotoluene (TNT) is structurally related to the rat liver carcinogen 2,4-dinitrotoluene (technical grade), and both compounds are known to be mutagenic to bacteria in vitro. TNT is therefore established as a potential rodent carcinogen; the present paper describes experiments designed to assess if this potential is likely to be expressed in appropriately exposed animals. TNT gave a negative response in the mouse bone marrow micronucleus assay and in an in vivo/in vitro rat liver assay for unscheduled DNA synthesis (UDS). In the latter assay animals are exposed to the test chemical in vivo and their hepatocytes subsequently evaluated for UDS in vitro. The negative response observed for TNT in the liver assay at dose-levels up to 1000 mg/kg was accompanied by a positive response for the hepatocarcinogen 2,4-dinitrotoluene at the lower dose-level of 200 mg/kg. In contrast, the dinitro compound gave a negative response in the micronucleus assay, as was also observed for TNT. It is concluded that the negative response observed for TNT in the liver assay indicates that it is unlikely to be a rat hepatocarcinogen. Nonetheless, high levels of methaemoglobin were observed in the TNT-treated rats and their urine was coloured red. These facts, together with the known toxicities of this agent suggest a possible carcinogenic hazard to the haemopoetic and urinary tissues of animals exposed chronically to it at toxic dose-levels.
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  • 150
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    Archives of toxicology 57 (1985), S. 53-55 
    ISSN: 1432-0738
    Keywords: Behavior ; Brain ; Catecholamines ; Serotonin ; Styrene ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Male albino rats were administered styrene in groundnut oil, PO at doses of 100 mg and 200 mg/kg body weight daily for 14 consecutive days. No neurological deficit was observed in any animal during the course of the experiment. Mean % avoidance response (learning) for each treated group, from day 1 to day 4 of conditioned avoidance response training, revealed a general increase. Styrene significantly increased the % avoidance response at both doses as compared to controls, although no definite dose-response relationship was evident. No significant difference was noted in the spontaneous locomotor activity and regional brain catecholamine levels, between controls and treated rats of either dose. Serotonin levels in hippocampus, hypothalamus, and mid-brain were significantly raised at the higher dose of styrene. Therefore, elevated serotonin levels in these brain regions may account for styrene-induced learning.
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  • 151
    ISSN: 1432-1106
    Keywords: Rat ; Luminance detector ; Darkness detector ; Pupil ; Sympathectomy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary In order to identify the pretectal nucleus which contains pupillomotor cells in the rat, cells were sought which were sensitive to changes in luminance level at the eye. Two types were found: Luminance detectors which showed a graded increase in firing with increase in luminance, and darkness detectors which showed a graded increase in firing rate with graded dimming of luminance intensity. All luminance detectors were located in the olivary pretectal nucleus, whereas darkness detectors were located in the posterior pretectal nucleus. Consensual pupil responses were recorded in conscious normal and sympathectomised rats using an infra-red sensitive T.V. pupillometer. Pupil diameter varied 2mm in an approximately linear fashion over six log units range in luminance intensity. Sympathectomy produced a general constriction of the pupil, but the overall response to light was unaffected. The changes in pupil size occurred over the same range of luminance that the firing rates of both luminance and darkness detectors changed. The olivary pretectal nucleus may therefore be involved in pupilloconstruction in the light, and the posterior pretectal nucleus, with pupillodilation in the dark.
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  • 152
    ISSN: 1432-1106
    Keywords: Rat ; Nucleus reticularis gigantocellularis ; Reticulospinal ; Laminae I, II and IX
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary We have used the autoradiographic method to study the organization of spinal projections from the gigantocellular reticular nucleus in the rat. Of particular note was the evidence obtained for projections to laminae I, II and IX. Reticular projections to laminae I and II arise more rostrally in Gi than those to lamina IX. Projections to laminae III–VIII and X as well as to autonomic nuclei have also been documented. Our results suggest that the gigantocellular reticular nucleus of the rat can be subdivided on connectional grounds.
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  • 153
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    Experimental brain research 58 (1985), S. 183-189 
    ISSN: 1432-1106
    Keywords: Olivocerebellar projection ; Axonal branching ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Axonal branching in the olivocerebellar projection was investigated using the retrograde fluorescent double-labelling method. Combinations of true blue and diamidino yellow injections (50 nl) were made in the cerebellar cortex of anaesthetized rats to investigate branching within single longitudinal zones and branching between such zones. The topographical arrangement of the projection was similar to that previously described, but additionally it was found that lateral parts of the inferior olive project more rostrally within a longitudinal zone and medial parts project more caudally in the same zone. Double-labelled olivary neurones, with axons branching rostrally and caudally within a single zone, were found to lie in an intermediate position between the two groups of single-labelled neurones. No such double-labelled neurones occurred when branching between zones was investigated. The correlation between these anatomical findings and earlier physiological work is discussed.
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  • 154
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    Experimental brain research 57 (1985), S. 256-263 
    ISSN: 1432-1106
    Keywords: Swallowing ; Medullary swallowing neurons ; Nucleus of the solitary tract ; Unit activity (extracellular microelectrodes) ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The aim of the present study was to identify the central structures involved in the organization of the swallowing reflex in the rat. Using concentric bipolar electrodes, the medulla and pons were systematically explored in order to determine which central areas responded to stimulation by inducing swallowing. These areas, which were located in the dorsal medulla oblongata, were the solitary tract, the nucleus of the solitary tract (NST) and the adjacent reticular formation. Stimulation of the ventral ponto-medullary regions was ineffective with regard to the initiation of the swallowing reflex. The activity of medullary swallowing neurons was recorded using extracellular microelectrodes. These swallowing neurons responded with a burst of spikes (swallowing activity) which was closely linked to the swallowing reflex elicited by stimulation of the superior laryngeal nerve (SLN). Under SLN stimulation, the activity of some of the swallowing neurons furthermore showed an initial response consisting of 1 or 2 spikes after a brief latency. According to their location and the latency of their initial response, swallowing neurons were divided into two groups. Group I neurons were located in a dorsal area of the medulla oblongata corresponding to the NST and the adjacent reticular formation. All these neurons exhibited an initial response with a very short latency (1 to 4 ms), the swallowing activity of most of these neurons started before the onset of the swallowing motor sequence. Group II neurons were located either in a ventral area corresponding to the nucleus ambiguus and the surrounding reticular formation or in a dorsal and medial area corresponding to the hypoglossal nucleus and its vicinity. Some of these neurons also exhibited an initial response to SLN stimulation, but with a longer latency (7–12 ms). Motor paralysis of the animal (performed by curare injection) did not affect the swallowing activity of the neurons belonging to either group. Thus, the swallowing activity of the medullary neurons studied was a truly central activity. It is concluded that the swallowing neurons studied belonged to the medullary swallowing center; the group II neurons were motoneurons and interneurons forming the efferent stage of the swallowing center, and the group I neurons were the interneurons which largely belong to the center which programs the swallowing motor sequence.
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  • 155
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    Experimental brain research 57 (1985), S. 537-546 
    ISSN: 1432-1106
    Keywords: Substance P ; Facial nucleus ; Medullary reticular formation ; Axo-dendritic contacts ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The distribution, origin and fine structure of substance P-like immunoreactive (SPI) nerve terminals in the facial nucleus of the rat were investigated by means of immunocytochemistry. SPI-terminals were concentrated in the intermediate and dorsal subnuclei of the facial nucleus. Hemi-transection of the brainstem just rostral to the facial nucleus or at the most caudal level of the medulla oblongata did not cause any change of SPI-terminals in the facial nucleus. Electrical destruction of the various parts of the medulla oblongata clearly demonstrated that SPI-terminals in the intermediate subnucleus were supplied contralaterally from the SPI-neurons in the dorsomedial part of the medullary reticular formation. Most of the SPI-terminals (85%) in the intermediate subnucleus of the facial nucleus were observed to make asymmetric synaptic contacts with large dendrites (mean diameter; 1.26 μm). It was supposed that the contact sites are located on proximal parts of the dendrite. A few SPI-terminals (6%) formed axo-somatic contacts with large perikarya filled with numerous cytoplasmic organelles.
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  • 156
    ISSN: 1432-1106
    Keywords: Hippocampus lesion ; Partial reinforcement ; Delay of reinforcement ; Inter-trial interval ; Inter-event interval ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Two experimental procedures were employed to establish the reason why hippocampal lesions apparently block the development of tolerance for aversive events in partial reinforcement experiments, but do not do so in partial punishment experiments. Rats were trained to run in a straight alley following hippocampal lesions (HC), cortical control lesions (CC) or sham operations (SO), and resistance to extinction was assessed following differing acquisition conditions. In Experiment 1 a 4–8 min inter-trial interval (ITI) was used. Either every acquisition trial was rewarded immediately (Continuous Reinforcement, CR), or only a randomly selected half of the trials were immediately rewarded, the reward being delayed for thirty seconds on the other trials (Partial Delay, PD). This delay procedure produced increased resistance to extinction in rats in all lesion groups. In Experiment 2 the ITI was reduced to a few seconds, and rats were trained either on a CR schedule, or on a schedule in which only half the trials were rewarded (Partial Reinforcement, PR). This form of partial reinforcement procedure also produced increased resistance to extinction in rats in all lesion groups. It thus appears that hippocampal lesions only prevent the development of resistance to aversive events when the interval between aversive and subsequent appetitive events exceeds some minimum value.
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  • 157
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    Experimental brain research 59 (1985), S. 559-569 
    ISSN: 1432-1106
    Keywords: Rat ; Superior colliculus ; Visual neglect ; Field defect ; Striate cortex
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Previous work has been shown that rats with lesions of the superior colliculus fail to respond to distracting visual stimuli presented in the peripheral field while the animals are running towards a central stimulus. To assess how far this peripheral neglect is due to an attentional deficit, rats were trained before operation to obtain reward by running towards either peripheral or central lights that were presented when the animals' heads were stationary in a known position. Response to stimuli presented 120 deg from the midline was severely impaired after removal of the superior colliculus: the animals behaved as if they had difficulty in detecting the onset of the light. In contrast, response to stimuli 40 deg from midline was unaffected. Control lesions of striate cortex did not significantly impair performance at any position. The finding that collicular animals were impaired at responding to stimuli in the far periphery, that were not irrelevant distractors but instead predicted reward, suggests that one component of the visual neglect produced by damage to the superior colliculus in rats may be a sensory deficit in the far peripheral field. In addition, comparison with previous results indicates that training to attend to visual stimuli in more central regions does improve performance, as would be expected if the deficit were an attentional one. It is therefore argued that collicular neglect in rats should be regarded as a multicomponent impairment.
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  • 158
    ISSN: 1432-1106
    Keywords: Granule cells ; Dendrites ; Golgi stain ; Dentate gyrus ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The dendritic morphology of Golgistained hippocampal dentate granule cells was evaluated by measuring the amount and location of dendrite, and the number of length of dendritic branches. Granule cells with somata in the superficial third of the granule cell layer had substantially more dendritic material than those with somata in the deep portions of the cell layer; this difference occurred throughout the extent of the molecular layer. Superficial cells also had different dendritic branching patterns and wider dendritic fields than did cells located in the deeper two-thirds of the granule cell layer. These results indicate that the position of neurons within the cell layer should be taken into account when quantifying the dendritic fields of dentate granule cells.
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  • 159
    ISSN: 1432-1106
    Keywords: Antidromic activation ; Latency variation ; Axonal excitability ; Paraventricular nucleus ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Magnocellular neurosecretory cells were antidromically identified in the hypothalamic paraventricular nucleus (PVN) of urethane-anesthetized, ovariectomized female rats following electrical stimulation of the neurohypophysis. Seventy-one cells with a tonic pattern of spontaneous discharge were distinguished and used to examine the relationships between the measures of antidromic spike latency, activation threshold and discharge rate. The discharge rate was artificially modulated by either microiontophoresis of glutamate or antidromic stimulation of the neurohypophysis. In all the PVN cells with tonic activity, the latency lengthened and the threshold increased as a function of the discharge rate. Activation of individual cells by microiontophoresis of glutamate was effective, as was simultaneous activation of many PVN cells by antidromic stimulus. Similar relationships between the discharge rate and the parameters of antidromic activation were seen in 3 cells, when their rates varied spontaneously over a wide range without manipulation. These data suggest that the excitability of axons of presumed oxytocinergic cells in the PVN-neurohypophyseal system are influenced by their prior activity, probably through metabolic changes in individual axons.
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  • 160
    ISSN: 1432-1106
    Keywords: GABAergic neurons ; Accessory optic nuclei ; Pretectal nuclei ; Gerbil ; Rat ; Visual system
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The enzyme glutamic acid decarboxylase (GAD) has been localized in sections of rodent brains (gerbil, rat) using conventional immunocytochemical techniques. Our findings demonstrate that large numbers of GAD-positive neurons and axon terminals (puncta) are present in the visual relay nuclei of the pretectum and the accessory optic system. The areas of highest density of these neurons are in the nucleus of the optic tract (NOT) of the pretectum, the dorsal and lateral terminal accessory optic nuclei (DTN, LTN), the ventral and dorsal subdivisions of the medial terminal accessory optic nucleus (MTNv, MTNd), and the interstitial nucleus of the posterior fibers of the superior fasciculus (inSFp). The findings indicate that 27% of the NOT neurons are GAD-positive and that these neurons are distributed over all of the NOT except the most superficial portion of the NOT caudally. The GAD-positive neurons of the NOT are statistically smaller (65.9 μm2) than the total population of neurons of the NOT (84.3 [j,m2) but are otherwise indistinguishable in shape from the total neuron population. The other visual relay nuclei that have been analyzed (DTN, LTN, MTNv, MTNd, inSFp) are similar in that from 21% to 31% of their neurons are GAD-positive; these neurons are smaller in diameter and are more spherical than the total populations of neurons. The data further show that a large proportion of the neurons in these visual relay nuclei are contacted by GAD-positive axon terminals. It is estimated that approximately one-half of the neurons of the NOT and the terminal accessory optic nuclei receive a strong GABAergic input and have been called “GAD-recipient neurons”. Further, the morphology of the GAD-positive neurons combined with their similar distribution to the GAD-recipient neurons suggest that many of these neurons are acting as GABAergic, local circuit neurons. On the other hand, the large number of GAD-positive neurons in the NOT and MTN (20–30%) in relation to estimates of projection neurons (75%) presents the possibility that some may in fact be projection neurons. The overall findings provide morphological evidence which supports the general conclusion that GABAergic neurons play a significant role in modulating the output of the visually related NOT and terminal accessory optic nuclei.
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    Experimental brain research 57 (1985), S. 471-479 
    ISSN: 1432-1106
    Keywords: Rat ; Lateral geniculate nucleus ; Thalamic reticular nucleus ; Bursts ; Inhibition ; Receptive fields
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Two-shock inhibition, a feature of 98 of 100 P cells recorded in the dorsal lateral geniculate nucleus of the normal rat, was not observed in 91 of 140 geniculate cells after an electrolytic lesion had been made in the adjacent visually responsive thalamic reticular nucleus. Nine geniculate cells recorded both before and after a reticular lesion had their initial inhibition abolished or substantially reduced after the lesion. The reticular lesion eliminated the bursts of spikes which normally terminate periods of inhibition following electrical or photic stimulation but caused no other changes in receptive field organization of geniculate cells. We conclude that the visually responsive region of the thalamic reticular nucleus in the rat is responsible for the profound two-shock inhibition and for the post-inhibitory bursts which are normal properties of relay cells of the dorsal lateral geniculate nucleus.
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    Annals of hematology 50 (1985), S. 109-112 
    ISSN: 1432-0584
    Keywords: Sudanophilia ; Rat ; Lymphocytes
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary A significant proportion of large lymphocytes in laboratory rats is stained with Sudan black B. The increase in the counts of sudanophilic blood lymphocytes over control values indicated reliablely the recovery of lymphocytic function even when total lymphocyte, small or large lymphocyte counts were normal or reduced.
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  • 163
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    Acta neuropathologica 65 (1985), S. 209-216 
    ISSN: 1432-0533
    Keywords: Hydrocephalus ; β,β′-Iminodipropionitrile ; Rat ; Guinea pig
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary β,β′-Iminodipropionitrile (IDPN), a neurotoxic compound known to induce swellings in the proximal internodes of sensory and motor axons in several parts of the central nervous system (CNS), was also found to cause hydrocephalus in rats and guinea pigs. In both species, ventricular dilatation was observed within 1 week following a single i.p. injection of IDPN. While in rats the severity of hydrocephalus correlated with dose and duration of IDPN exposure, in guinea pigs studies with high doses yielded inconclusive results, and no significant temporal correlation was noted. Parallel investigations with another peurotoxic agent, acrylamide, in rats, and with IDPN in cats failed to demonstrate any change in size and shape of the cerebrospinal fluid (CSF) pathways. No signs of spontaneously occurring hydrocephalus were found in control animals. In both rats and guinea pigs intoxicated with IDPN, macroscopic and microscopic findings were consistent with the diagnosis of communicating hydrocephalus. Treatment of hydrocephalic rats with acetazolamide (500 mg/kg) markedly attenuated ventricular distention, suggesting that an overproduction of CSF by the choroid plexus is responsible for the communicating hydrocephalus following IDPN intoxication.
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  • 164
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    Development genes and evolution 194 (1985), S. 429-432 
    ISSN: 1432-041X
    Keywords: Tail bud ; Tail gut ; Gut ; Organogenesis ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary The formation of the tail portion of the primitive gut was investigated by light and electron microscopy in 10- and 11-day rat embryos. The observations permit the conclusion that the tail gut does not form as a posterior extension of the hindgut but originates from the tail bud mesenchyme by mechanism analogous to the secondary neurulation. It includes cell condensation, aquisition of apicobasal polarity and the radial, rosette-like arrangement around a central cavity. These cells bear the cytological characteristics of both the absorptive epithelial cells and the mesenchymal cells at their apical (adluminal) and abluminal ends respectively.
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  • 165
    ISSN: 1432-2072
    Keywords: Substance P ; Ventral mesencephalon ; Investigatory behavior ; Motor behavior ; Dopamine ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract In the present experiments the behavioral response to substance P (SP) microinfusion into the ventral tegmental area (VTA), substantia nigra (SN), and sensorimotor cortex (CX) was investigated in detail. The experiments were carried out using an eight-hole box to measure exploratory behavior and a video monitor for the analysis of spontaneous motor behavior. When infused into the VTA, SP (0.125, 0.5, 3.0 μg) augmented the frequency and total duration of hole-pokes, and tended to diminish the mean duration of hole-pokes. The strategy and organization of responses, as measured by the order of hole-visits and hole-switching, were unchanged by SP and there was no indication of stereotypy, measured by the number of hole-pokes per hole-visit. The open-field analysis revealed a marked increase in locomotion and rearing, both in the periphery and center of the arena; grooming was decreased by SP. The behavioral profile following SN infusions of SP (3.0 μg) was similar to that elicited by VTA infusions, with the exception that center rearing was not enhanced. SP administration into cortex (3 μg) had no significant effect on any behavioral measures. It is hypothesized that SP infused into the ventral mesencephalon results in an enhancement of approach response tendencies, suggesting that endogenous SP in this region may regulate spontaneous behavior. The possibility of an interaction between SP and meso-telencephalic dopamine neurons is discussed.
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  • 166
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    Psychopharmacology 85 (1985), S. 80-86 
    ISSN: 1432-2072
    Keywords: Conditioned suppression ; Drug stimuli ; Stimulus control ; Overshadowing ; Classical conditioning ; Operant behavior ; Drugs ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Rats were trained to press a lever under a variable-interval (VI) schedule of water reinforcement. After stable responding had developed, a 4.5-KHz tone (CS) was conditioned classically to a 2.5-mA electric shock (US) in groups of animals which had been given various psychoactive drugs or saline. Twenty-four hours later, a stimulus generalization test was conducted in the absence of drug; during this session, tones that varied in frequency around 4.5 KHz were presented while the animals were responding under the VI schedule. In animals conditioned under saline, all tones (non-differentially) suppressed responding which, however, recovered gradually over time. This suppressive effect was eliminated by lysergic acid diethylamide (LSD; 0.2 and 0.32 mg/kg), cocaine (20 mg/kg), diazepam (2.5 mg/kg), lisuride (0.08 mg/kg), mescaline (20 mg/kg) and 5-methoxy-N,N-dimethyltryptamine (4 mg/kg), and was attenuated by amphetamine (4 mg/kg), pentobarbital (15 mg/kg) and morphine (4 mg/kg). Atropine (10 mg/kg), scopolamine (1 mg/kg), clonazepam (0.5 mg/kg), and chlorpromazine (4 mg/kg) did not alter the suppressive effect of the tone. The serotonin antagonist BC-105 (6 mg/kg) reversed the effect of 0.2 mg/kg of LSD. These results suggest (1) that drug-induced stimuli may “overshadow” other (e.g., external) stimuli during classical conditioning and, (2) that drugs might affect behavior by altering processes (stimulus control or others) that do not simultaneously involve response or motor control.
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  • 167
    ISSN: 1432-2072
    Keywords: Clonidine ; Sedation ; Activity ; RHA/iop and RLA/iop ; Strains ; Adrenoceptors ; Stress ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract An hypothesis that repeated stress results in central changes in α2-adrenoceptor sensitivity was investigated using a behavioural test. Stressed (immobilisation for 2 h/day for 7 days) and unstressed rats from the RHA/iop and RLA/iop strains were tested for the sedative effects of the α2-adrenoceptor agonist clonidine on Y-maze behaviour. The measures used were number of lines crossed, arm entries and rearing. The stressed animals showed higher scores for line crossings and rearing; but the only significant difference between the strains was for rearing, which was higher for RHA/iop. Clonidine significantly depressed all the measures of activity. However, there was no evidence of an interaction of the drug with stress for any of the measures. It is concluded that neither repeated stress nor genetic differences in the ability to cope with stress influence the behavioural effects of clonidine. This suggests that stress responses are not related to the central α2-adrenoceptor system.
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  • 168
    ISSN: 1432-2072
    Keywords: d-Amphetamine ; Response rate ; Reinforcement efficacy ; Response topography ; Matching law ; Rate-dependency ; Variable-interval schedule ; Lever press ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract A mathematical model was used to describe the effects of amphetamine on the rate of a reinforced response in the rat. The model provides measures of reinforcement efficacy and response topography for behavior maintained by variable-interval reinforcement schedules. In this study the measured behavior was a lever press, the reinforcer was water, and the variable-interval schedules provided five different rates of reinforcement, ranging from about 20 to 660/h. In each session the rats were exposed to each of the five schedules, and as reinforcement rate increased, the rate of lever pressing increased in a negatively accelerated manner that was closely approximated by the equation for a rectangular hyperbola. Amphetamine changed responser rate and the parameters of the best-fitting hyperbolas. The 0.25–1.0-mg/kg doses increased response rate, and the parameter changes supported the interpretation that the increases were due primarily to an increase in reinforcement efficacy. The 2.0- and 3.0-mg/kg doses decreased response rates maintained by low reinforcement rates and increased response rates maintained by high reinforcement rates, and the parameter changes supported the interpretation that at higher doses amphetamine produced counteracting changes in reinforcement efficacy and response topography: reinforcement efficacy decreased, whereas response topography changed so as to increase response rates.
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  • 169
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    Psychopharmacology 85 (1985), S. 178-183 
    ISSN: 1432-2072
    Keywords: Δ9-THC stimulus ; Δ9(11)·THC ; THC receptor ; Drug response ; Blockage of drug discrimination ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Rats were trained in a water maze to discriminate between IP injections of 3 mg/kg Δ9- (Δ9(11)-THC) and its vehicle. Both Δ8- and Δ9(11) were generalized to the training drug. In contrast to our observations in rhesus monkeys, where Δ9-THC is at least 100 times less potent than Δ9-THC, Δ9(11) was found to be only seven times less potent in the rat. Relative potencies, expressed as the dosage at which 50% of the animals gave drug responses (ED50) were 1.8 mg/kg and 12.2 mg/kg for Δ9-THC and Δ9(11) respectively. Twenty-four hours after receiving 7×ED50=12 mg/kg Δ9 the tests showed intermediate results when conducted with the training dosage; 4×ED50=50 mg/kg Δ9-THC 48 h prior to the training dosage of 3 mg/kg Δ9-THC completely blocked drug-appropriate responses. Coinjection of ED50 dosages of Δ9- and Δ9(11)-THC led to 90% drug responses, demonstrating the additivity of the cannabis-like effect of both cannabinoids. Differences in the individual sensitivity of the rats to the tested cannabinoids were observed. Findings are interpreted in terms of the receptor mechanism for cannabis-like activity.
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  • 170
    ISSN: 1432-2072
    Keywords: Neurotensin ; Ventral mesencephalon ; Investigatory behaviour ; Motor behavior ; Dopamine ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The present experiments examined in detail the behavioral response to microinfusions of neurotensin (NT) into the ventral tegmental area (VTA), substantia nigra (SN) and hippocampus (HPC). The behavioral apparatus consisted of an eight-hole box in which investigatory and spontaneous motor behavior were recorded. Three doses (0.175, 0.5, 4.0 μg) of NT were injected into the VTA. The main effect of NT was a strong augmentation of rearing (frequency and duration) both in the periphery and center of the arena, accompanied by a small increase in locomotion and decreased grooming. NT had no effect on the strategy, organization, or duration of exploration but did augment frequency of hole visits towards the end of the session. NT injected into the SN and HPC had no effect on investigatory and spontaneous behavior with the exception of an increase in peripheral locomotion after HPC-NT injections. The results are discussed in terms of a modulatory role of endogenous NT on mesolimbic dopamine neurons.
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  • 171
    ISSN: 1432-2072
    Keywords: Cimetidine ; Rantidine ; Imidazole ; (±) NPA ; Penile erections ; Stretching and yawning ; Stereotyped behaviour ; DA receptors ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Cimetidine injected IP 15 min before (±) N-n-propylnorapomorphine (NPA) antagonized in dose-dependent fashion the penile erections (PE) and stretching and yawning (SY) induced by this typical dopaminergic agonist in male rats. Ranitidine, which acts on H2 histamine receptors in much the same way as cimetidine despite its lack of an imidazole ring, failed to produce the same effect. On the other hand, imidazole itself was similar to cimetidine in antagonizing PE and SY induced by (±) NPA, whether injected IP or ICV. Neither imidazole nor cimetidine antagonized the stereotyped behaviour (SB) induced by (±) NPA. Indeed, imidazole reduced the latency of this response. A mechanism which may underly these effects is discussed, as well as the possible preclinical use of this test in animals.
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  • 172
    ISSN: 1432-2072
    Keywords: Heroin ; Intravenous self-administration ; Methyl naloxonium chloride ; Opiates ; Reward ; Nucleus accumbens ; Ventral tegmental area ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract A quaternary derivative of naloxone, methyl naloxonium chloride (MN), was administered intracerebrally to rats trained to self-administer heroin intravenously. Increases in intravenous (IV) heroin self-administration rates were found following injections of low doses of MN into the nucleus accumbens (N.Acc), but not following injections of low doses of MN into the ventral tegmental area (VTA). These results were interpreted to suggest that the rewarding properties of IV heroin were decreased following N.Acc opiate receptor blockade. The relative insensitivity of the VTA to MN treatment was taken to suggest that VTA opiate receptors are either not essential or play a secondary role in mediating IV heroin self-administration. The present data support the notion that post-synaptic N.Acc opiate receptors play a crucial role in maintaining IV heroin self-administration.
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  • 173
    ISSN: 1432-2072
    Keywords: Acetylcholinesterase ; Acetylcholinesterase inhibitors ; Soman ; Schedule-controlled behavior ; Fixed interval ; Gastrointestinal tract ; Brain ; Tolerance ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Intraperitoneal (IP) administration of the acetylcholinesterase inhibitor, soman (10–40 μg/kg), suppressed in a dose-related manner response rates in rats maintained under a multiple fixed-interval 50-s fixed-ratio 25 schedule of food delivery. Chronic administration of soman at weekly intervals resulted in tolerance to the response. When soman administration was separated by 2–5 weeks in individual rats, the suppressive effects of the agent again became apparent. Analysis of acetylcholinesterase activity revealed that enzyme inhibition was limited to gastrointestinal areas near the site of injection. There was no significant effect on brain acetylcholinesterase even following IP injection of doses which completely suppressed responding. The IP route may be useful for studying tolerance and other chronic effects of soman without producing generalized toxicity.
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  • 174
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    Psychopharmacology 87 (1985), S. 219-224 
    ISSN: 1432-2072
    Keywords: Propranolol ; Beta-adrenergic blocker ; Differential reinforcement of low rates of response (DRL) ; Differential punishment of high rates of response (DPH) ; Chlordiazepoxide ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Ten rats were trained to lever press for food reward on a schedule of differential reinforcement of low rates of response with a 20-s criterion (DRL 20). Ten more were trained on a new schedule of punishment, designed to be comparable to DRL 20 — differential punishment of high rates of response (DPH 20). Under this schedule, responses with a latency of 20 s or more earned food rewards, while those of less than 20 s were followed by food reward and brief electric footshock. After 42 sessions, rats on each schedule showed temporal discrimination in the distribution of inter-response times. The effects on these baselines of the anxiolytic chlordiazepoxide (CDP; 1 mg/kg IP) and the beta-blocker propranolol (2, 5 and 10 mg/kg IP) were investigated. Both drugs reduced numbers of responses reaching criterion (criterion resonses) in DPH, CDP increasing total responses. CDP acted similarly under DRL, but propranolol only affected performance at the highest doese, which reduced criterion responses, probably because of changes in total responding. Each drug increased response bursts. It is concluded that propranolol can exert a disinhibitory action in these schedules, although with some differences from that of the benzodiazepine CDP.
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  • 175
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    Psychopharmacology 87 (1985), S. 238-241 
    ISSN: 1432-2072
    Keywords: Conditioned taste aversion ; Vasopressin ; Vasopressin analogs ; Vasopressin antagonist ; Hypertension ; Apomorphine ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Rats injected SC with arginine vasopressin (AVP) following consumption of a milk solution developed a marked aversion to the taste of this solution. An analog of vasopressin devoid of pressor activity, dDAVP, was unable to induce conditioned taste aversion. The aversive stimulus properties of AVP were blocked by the vasopressor antagonist dPTyr(Me)AVP. This antagonist did not block apomorphine-mediated conditioned taste aversion. These results demonstrate that AVP induces conditioned taste aversion by interacting with vasopressor-like receptors.
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  • 176
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    Psychopharmacology 87 (1985), S. 225-232 
    ISSN: 1432-2072
    Keywords: Place conditioning ; Diazepam ; Meprobamate ; CGS 8216 ; Picrotoxin ; Sodium valproate ; Naloxone ; Reward ; Aversion ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The place conditioning paradigm was used to examine the reinforcing properties of diazepam. Rats were injeccted with diazepam (0.5–5.0 mg/kg, IP) and 30 min later were confined for 30 min to one side of a shuttle box, in which each of the two compartments had distinctive features. On alternate (control) days they received vehicle injections and were confined for 30 min to the opposite side. At almost all doses tested, diazepam produced place preference for the distinctive compartment that had been previously associated with the drug. Preference for the drug side developed regardless of whether diazepam was paired or unpaired with the least-preferred side, and regardless of whether testing was carried out in the undrugged or in the drugged state. The rats preferred the drug side over a novel compartment, but they did not change their initial preference for the side when diazepam was given after removal from the training box. Animals injected with meprobamate (70 mg/kg, PO), a non-benzodiazepine anxiolytic, also developed conditioned preference for the drug side, comparable to that seen following cocaine hydrochloride (10 mg/kg, IP). The diazepam (2.5 mg/kg)-induced place preference was antagonized by CGS 8216 (3 mg/kg, IP), picrotoxin (2 mg/kg, IP) and naloxone (0.8 mg/kg, SC), injected 3 min before and 15 and 20 min after diazepam respectively. Sodium valproate (200 mg/kg, IP) did not influence diazepam (1 mg/kg)-induced place preference. Sodium valproate by itself had marginal effects on place conditioning. Picrotoxin and naloxone, but not CGS 8816, produced place aversion which, in the case of picrotoxin, was due to state dependent learning. The results provide a clear indication that the place preference paradigm is valid as a test for evaluating appetitive properties of minor tranquilizers. They suggest that the rewarding effects of diazepam are mediated through central benzodiazepine receptors. Wheter GABA and/or endogenous opioid peptides are involved in the reinforcing properties of diazepam remains an open question.
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  • 177
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    Psychopharmacology 87 (1985), S. 260-265 
    ISSN: 1432-2072
    Keywords: Active avoidance ; Nociception ; Spinal serotonin ; p-Chloroamphetamine ; 5,6-Dihydroxytryptamine ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The effects of selective lesions of the descending serotonergic (5-HT) pathways on analgesia and avoidance deficit induced by the 5-HT releasing compound p-chloroamphetamine (PCA, 2.5 mg/kg) were investigated in male rats. Intrathecal injection of 5,6-DHT (20 μg/rat) reduced the uptake of labelled 5-HT into spinal synaptosomes by approximately 85% but did not significantly affect the uptake of noradrenaline. The lesions produced a significant hyperalgesia and strongly attenuated the analgesic effect of PCA in the hot-plate test. In the flinch-jump test 5,6-DHT lesioned rats receiving PCA did not differ from the saline control group. Spinal lesioning did not, however, affect one-way active avoidance performance and did not prevent the marked impairment of avoidance performance induced by PCA. Thus, the avoidance deficit caused by PCA is independent of the descending serotonergic pathways and of the analgesia induced by PCA. These results support the view of a differential involvement of the ascending and descending serotonergic projections in behavioural processes controlled by aversive stimuli.
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  • 178
    ISSN: 1432-2072
    Keywords: Exploration ; Locomotor activity ; Sedation ; Chlordiazepoxide ; Benzodiazepine ; CL 218,872 ; Benzodiazepine antagonists ; Ro 15-1788 ; CGS 8216 ; Rat ; Mouse
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The effects of CL 218,872, initially classified as a non-sedative anxiolytic, were investigated and compared with those of chlordiazepoxide in the holeboard. The ability of two drugs that antagonise the effects of benzodiazepines, CGS 8216 and Ro 15-1788, to reverse the effects of CL 218,872 and chlordiazepoxide were also investigated, to see whether their effects might be mediated via benzodiazepine receptors. CL 218,872 (10 mg/kg) was found to be significantly sedative in both mice and rats (i.e., both locomotor activity and head-dipping were significantly decreased). In mice, the effects of CL 218,872 and of chlordiazepoxide were very similar over a range of doses, except that the stimulatory effect seen with low doses of chlordiazepoxide on head-dipping just failed to reach significance with CL 218,872. This study is in agreement with recently published results from different tests showing that sedative effects can be obtained with doses of CL 218,872 that are low and not much higher than those leading to anxiolysis. The sedative effects of both CL 218,872 (10 mg/kg) and chlordiazepoxide (20 mg/kg) were significantly reversed by RO 15-1788 (10 and 20 mg/kg) and CGS 8216 (10 mg/kg), suggesting that their effects are mediated via benzodiazepine receptors. The increase in head-dipping seen with chlordiazepoxide (2.5 mg/kg) was also reversed by RO 15-1788 and CGS 8216.
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  • 179
    ISSN: 1432-2072
    Keywords: DA D-1 receptors ; DA D-2 receptors ; Circling behaviour ; Dopamine agonists ; Dopamine antagonists ; 6-OHDA lesions ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The antagonistic effect of dopamine (DA) D-1 and D-2 antagonists against circling behaviour induced by various DA agonists in 6-OHDA-lesioned rats has been investigated. DA D-1/D-2 selectivity of agonists in vitro was measured by the stimulatory effect on DA-sensitive adenylate cyclase in rat striatal homogenates (D-1), the inhibitory effect on electrically-induced release of 3H-DA in rabbit striatal slices (D-2) and the affinity to 3H-piflutixol (D-1) and 3H-spiroperidol (D-2) binding sites in rat striatal membranes. The contralateral circling behaviour induced by the DA D-1 agonist SK & F 38393 was blocked by the DA D-1 antagonist, SCH 23390, and by the mixed DA D-1/D-2 antagonist cis(Z)-flupentixol, but was not influenced by the DA D-2 antagonists spiroperidol and clebopride. In contrast, circling behaviour induced by the preferential DA D-2 agonists pergolide and LY 171555 was blocked by clebopride, spiroperidol, and cis(Z)-flupentixol, but weakly or not influenced by SCH 23390. Apomorphine-induced circling behaviour was blocked by cis(Z)-flupentixol, partially antagonized by SCH 23390 and clebopride but not inhibited by spiroperidol, although the time-course of circling was changed. Combinations of SCH 23390 with spiroperidol or clebopride in low doses completely blocked the effect of apomorphine. These results indicate that DA D-1 and D-2 receptors mediate circling behaviour through separate mechanisms which can be independently manipulated with respective agonists and antagonists. Furthermore, the results indicate that both DA D-1 and D-2 receptors are involved in the effect of apomorphine, since selective antagonists induced maximally 50% inhibition. Complete blockade was only found in combination experiments and by the mixed D-1/D-2 antagonists cis(Z)-flupentixol, cis(Z)-clopenthixol, and clozapine.
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  • 180
    ISSN: 1432-2072
    Keywords: GABAergic hypothesis of anxiolytic action ; Muscimol ; Baclofen ; Chlordiazepoxide ; Picrotoxin ; Bicuculline ; Spontaneous alternation ; Response to stimulus change ; Exploration ; Novelty ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Two methods were used to test rats' responses to novelty in the T-maze: (1) a test of spontaneous alternation allowing separate measurement of place and body turn alternation; and (2) a test of entry into an arm of changed brightness (“response to stimulus change”). Chlordiazepoxide reduced spontaneous alternation by specifically weakening body turn alternation and eliminated the response to stimulus change. These findings are similar to those previously reported for the barbiturate sodium amylobarbitone. The same pattern of change in the two tests was seen after a low dose of the GABAA agonist muscimol (0.00125 mg/kg); when the dose of muscimol was raised (0.01 and 0.25 mg/kg), place alternation was also reduced. Picrotoxin but not bicuculline (both GABAA blockers) reversed the effects of muscimol and partially those of chlordiazepoxide on the response to stimulus change; in the spontaneous alternation test picrotoxin only marginally affected the response to 0.25 mg/kg muscimol and actually enhanced the effect of 0.000125 mg/kg. The GABAB agonist baclofen (1 mg/kg) acted in the test of response to stimulus change like chlordiazepoxide and muscimol; however, when baclofen was combined with muscimol, the two drugs tended to show mutual blocking. These results are generally consistent with the hypothesis that GABAergic mechanisms play a role in anxiolytic behavioural activity, but many details are difficult to explain.
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  • 181
    ISSN: 1432-2072
    Keywords: Delayed alternation ; Spatial memory ; Cortex ; Dopamine ; Noradrenaline ; 5-Hydroxytryptamine ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Seventeen male Sprague-Dawley rats were trained to eight to nine correct responses on a delayed spatial alternation test performed on alternate days in a T-maze. Locomotor activity in an observation box was scored on 2 consecutive days. The animals were killed 2 weeks after the end of behavioural testing and dopamine (DA), noradrenaline (NA), 5-hydroxytryptamine (5HT), the DA metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) and the 5HT metabolite, 5-hydroxyindoleacetic acid (5HIAA) determined in cortex, hippocampus, striatum and hypothalamus. Cortical concentrations of both DA and NA correlated negatively and significantly with the number of errors made in learning the alternation task, though the latter correlation was less striking and became negligible after the correlation between DA and NA was partialled out. Concentrations of DA and NA in the other regions did not correlate significantly with errors. None of the other neurochemical variables correlated significantly with either errors or locomotor activity, except for hypothalamic HVA concentration which showed a marginally significant correlation with locomotor activity. The above results, together with effects of brain lesions reported by other authors, strongly indicate that cortical catecholamines facilitate learning in the normal non-drug-treated rat.
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  • 182
    ISSN: 1432-2072
    Keywords: γ-Aminobutyrate (GABA) ; GABA and GABA agonists ; Chlordiazepoxide ; Amylobarbitone ; Picrotoxin ; Bicuculline ; β-Carbolines ; Muscimol ; Baclofen ; Punished barpressing ; Anxiety ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Rats were trained to press a bar for sucrose reward on a random-interval (RI) schedule and footshock punishment was then introduced for 3-min intrusion periods (signalled by a tone) on an independent RI schedule. Shock intensity was individually adjusted to produce stable intermediate levels of response suppression during the tone for each animal. Groups of animals were then allocated to a number of separate experiments in which they were systemically injected with anxiolytics (chlordiazepoxide HCl or sodium amylobarbitone), GABA antagonists (picrotoxin or bicuculline), the GABAA agonist muscimol, the GABAB agonist baclofen, an antagonist (RO 15-1788) at the benzodiazepine receptor and, an inverse agonist (FG 7142) at this receptor. The results showed that the alleviation of punishment-induced suppression of barpressing produced by chlordiazepoxide was blocked or partially blocked by RO 15-1788, picrotoxin and bicuculline but not by FG 7142; that picrotoxin (but not FG 7142) increased the suppression of responding by punishment; that neither muscimol nor baclofen affected responding on their own, but their combination weakly but reliably released punished responding from suppression; and that the anti-punishment effect of amylobarbitone was unaffected by either picrotoxin or bicuculline, though the barbiturate reversed the punishment-enhancing effect of picrotoxin. These results are discussed in the light of the hypothesis that anxiolytic behavioural effects are due to increased GABAergic inhibition.
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  • 183
    ISSN: 1432-2072
    Keywords: 5-HT antagonist ; LSD antagonist ; Drug discrimination ; Anxiety ; 5-HTP ; Head twitch ; Conflict behavior ; Hypothermia ; Ritanserin ; Pirenperone ; Chlordiazepoxide ; Diazepam ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The newly synthesized compound and putative 5-HT2 antagonist ritanserin, but not the structurally related compound R 56413, resembles pirenperone in that it acts as a pure antagonist in an LSD-saline drug discrimination assay in the rat. Ritanserin exceeded pirenperone in terms of behavioral specificity; the lowest effective dose of ritanserin in antagonizing LSD was one order of magnitude higher than that of pirenperone, but the compound depressed rate of operant responding only at doses that were about 1000-fold higher than those at which pirenperone was effective. Ritanserin exerted effects in an open field test which were reminiscent of anxiolytic drug activity in the rat; its effects were greater than those of pirenperone, R 56413 and the benzodiazepines chlordiazepoxide and diazepam. The results of experiments on antagonism of 5-HT-induced hypothermia and of the 5-HTP-induced headtwitch response fail to support the possibility that the putative anxiolytic effects of ritanserin in the rat can be ascribed simply to a pharmacologically defined action at 5-HT receptors.
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  • 184
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    Psychopharmacology 86 (1985), S. 344-347 
    ISSN: 1432-2072
    Keywords: β-Carboline ; Benzodiazepines ; Anxiety ; Food intake ; Aggression ; FG 7142 ; Pentylenetetrazol ; Caffeine ; Lactation ; Maternal behaviour ; Sex hormones ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Mother rats nursing large litters are hyperphagic, aggressive towards conspecifics, and show less freezing behaviour than non-maternal animals. These naturally occurring adaptations resemble those elicited by benzodiazepine treatment in virgin rats, indicating a common neurochemical change in the brains of mother rats and benzodiazepine-treated virgins. In line with this hypothesis, it was found that three functional benzodiazepine antagonists (FG 7142, pentylenetetrazol, caffeine) decreased food intake, lowered aggression and strengthened freezing in lactating mother rats. These psychopharmacological observations support the idea that GABA neurotransmission is enhanced during motherhood in the rat.
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  • 185
    ISSN: 1432-2072
    Keywords: CGS 8216 ; DMCM ; FG 7142 ; Food intake ; Midazolam ; Palatability ; Ro15-1788 ; Satiety ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Non-deprived rats were familiarised with a highly palatable diet until baseline consumption in a 60-min daily access period had stabilised. The benzodiazepine receptor agonist midazolam (1.25–10.0 mg/kg, IP) produced a large, dose-related increase in food consumption during the first 30 min of access. It also produced significant, short-term hyperphagia in animals which had been partially pre-satiated on the diet before drug administration, an effect which was reversible by the benzodiazepine receptor antagonist Ro15-1788. Administered alone, Ro15-1788 (1.25–10.0 mg/kg, IP) had no intrinsic activity in the food consumption test. In contrast, CGS 8216 (2.5–40.0 mg/kg, IP) produced a marked dose-related suppression of food intake. This anorectic effect was shared by two benzodiazepine receptor inverse agonists, FG 7142 and DMCM, which also produced dose-dependent reductions in consumption. The effects on feeding produced by FG 7142 (20 mg/kg, IP) and DMCM (1.25 mg/kg, IP) were reversed by either Ro15-1788 (2.5 and 5.0 mg/kg) or midazolam (5.0 and 10.0 mg/kg). A matched anorectic effect produced by CGS 8216 (40 mg/kg) was not, however, reversed by either Ro15-1788 or midazolam. This suggests that at a high dose CGS 8216 may act by a mechanism different from that of the two inverse agonists. The feeding test described in the report proved sensitive to both hyperphagic and anorectic effects of drugs active at benzodiazepine receptors, pointing to a possible bi-directional control of palatable food consumption.
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  • 186
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    Journal of molecular medicine 63 (1985), S. 868-876 
    ISSN: 1432-1440
    Keywords: Distal nephrons ; Cellular heterogeneity ; Electrolyte excretion ; Furosemide ; Rat ; Kidney morphology ; Distale Nephrone ; Zelluläre Heterogenität ; Elektrolytausscheidung ; Furosemid ; Ratte ; Nierenmorphologie
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Zusammenfassung Die distalen Tubuli in der Nierenrinde gliedern sich nach der Macula densa in drei morphologisch verschieden gebaute Abschnitte: in die pars convoluta des distalen Tubulus (DCT), den Verbindungstubulus (CNT) und das corticale Sammelrohr (CCD). In den drei Segmenten sind insgesamt vier Zelltypen vorhanden: die DCT-Zelle, die CNT-Zelle, die Haupt-Zelle (P-Zelle) und die Schaltzelle (I-Zelle), die sich unter anderem an Hand der Ausbildung ihrer Zellmembranfläche unterscheiden lassen. In der DCT-, CNT- und P-Zelle ist in verschiedenem Ausmaß jeweils die basolaterale Membranfläche vergrößert, in der die Na-K-ATPase lokalisiert ist. In der I-Zelle ist die luminale Zellmembran vergrößert, in der wahrscheinlich eine H+-ATPase vorhanden ist. Bei längerdauernden Änderungen im Elektrolythaushalt treten in den Zellen strukturelle Anpassungserscheinungen auf, die vor allem das Ausmaß der aktiv transportierenden Membranflächen betreffen (basolaterale Membranflächen in DCT-, CNT- und P-Zellen; luminale Membran in I-Zellen). Die Veränderungen der basolateralen Membranfläche verhalten sich proportional zu den Änderungen der Na-K-ATPase-Aktivität und zeigen daher eine entsprechende Änderung der transzellulären Transportkapazität an. Morphologische Untersuchungen haben gezeigt, daß jeder Zelltyp nur auf für ihn spezifische Veränderungen im Elektrolythaushalt reagiert und erlauben daher gewisse Rückschlüsse auf die spezifische Rolle der einzelnen Zelltypen bei der Regulierung des Elektrolytausscheidung. Aus dem Muster der strukturellen Veränderungen läßt sich ableiten, daß bei bestimmten Zelltypen außer Hormonen offenbar auch die Elektrolytzusammensetzung der Tubulusflüssigkeit den transzellulären Transport beeinflußt. Daher müssen Veränderungen des Elektrolyttransports, die in einem Abschnitt spezifisch induziert werden (z.B. durch Furosemid), sich auch in nachgeschalteten Abschnitten auf den transzellulären Transport auswirken. Die zelluläre Heterogenität der distalen Abschnitte scheint eine differenzierte Regulierung der Elektrolytausscheidung unter unterschiedlichsten Bedingungen zu garantieren.
    Notes: Summary The distal segments beyond the macula densa — distal convoluted tubule, connecting tubule, cortical collecting duct — display cellular heterogeneity. The four different cell types, namely the DCT cell, CNT cell, the principal cell and intercalated cell differ mainly by the pattern of membrane amplification and they reveal also qualitative differences as to some cytoplasmic proteins. Each of the four cell types adapts to chronic changes in electrolyte metabolism with structural alteration, concerning essentially the membrane area over which the active transport step of the cell proceeds, in DCT-, CNT- and P-cells the basolateral cell membrane with the Na-K-ATPase, in intercalated cells the luminal cell membrane with a H+ ATPase. Since each cell type responds only to specific conditions with changes in membrane area and associated transcellular transport activity, morphological studies can help to determine the specific role of each cell type in the regulation of renal electrolyte excretion. Such investigations demonstrated that besides mineralocorticoid hormones the transport capacity of certain cells should depend on the solute composition of tubular fluid. Thus, changes in the transport pattern specifically induced in only one segment alters also the transport patterns of segments downstream. Cellular heterogeneity seems to guarantee the optimal regulation of renal electrolyte excretion.
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  • 187
    ISSN: 1573-9104
    Keywords: Soybean ; Rapeseed ; Wheat ; Protein fractions ; Protein efficiency ratio ; Digestibility ; Vegetable protein blends ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Agriculture, Forestry, Horticulture, Fishery, Domestic Science, Nutrition
    Notes: Abstract Blends of vegetable proteins were prepared to improve the nutritive value of these proteins. Soybean flour, rapeseed protein concentrate, whole wheat flour, soybean 2S+11S extract, wheat albumin-globulin + glutenin (AG+G) functions, and some of their blends were compared to casein for protein efficiency ratio (PER) and apparent digestibility coefficient (ADC). Autoclaving (1 h) soybean proteins was also studied. Casein and rapeseed protein concentrate gave the highest weight gains and PER. Other protein sources gave lower values for both PER (P〈0.05) and weight gain. The digestibility of all vegetable proteins was lower (P〈0.05) than that of casein. PER of soybean 2S+11S extract was significantly lower (P〈0.05) than that of soybean flour. Autoclaving significantly (P〈0.05) improved the PER of both soybean flour and 2S+11S extract. The ADC of autoclaved 2S+11S extract was similar (P〈0.05) to that of autoclaved soybean flour and significantly higher (P〈0.05) than that of 2S+11S extract. Soybean flour had the lowest (P〈0.05) ADC. Heat treatment destroyed antinutritional factors, probably trypsin inhibitors and/or haemagglutinins of soybean. This was accompanied by improvement in the nutritional value of protein. The four blends were chosen on the basis of amino acid composition, chromatography of proteolyzates and nutritive value of each fraction. The PER of wheat albumin-globulin and glutenin (AG+G) blend was similar (P〈0.05) to that of wheat flour and lower (P〈0.05) than that of all other blends used. Wheat AG+G+rapeseed protein concentrate and wheat AG+G+soybean flour blends gave the highest (P〈0.05) PER. Wheat AG+G improved the PER of 2S+11S extract and of soybean flour but decreased the PER of rapeseed protein concentrate. Wheat AG+G and wheat AG+G+rapeseed protein concentrate blends gave an ADC significantly higher (P〈0.05) than that of wheat AG+G blend containing soybean flour of 2S+11S extract. However, blending wheat AG+G with either 2S+11S extract of soybean flour improved ADC.
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  • 188
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    Journal of pharmacokinetics and pharmacodynamics 13 (1985), S. 1-12 
    ISSN: 1573-8744
    Keywords: sulfisoxazole ; cirrhosis ; pharmacokinetics ; volume of distribution protein binding
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The disposition of sulfisoxazole was studied in six male patients hospitalized with biopsy-proven Laennec's alcoholic cirrhosis and six normal, healthy volunteers. Four of the patients were restudied at a time their liver disease had improved clinically. On the average, compared to the normal group, the metabolism of sulfisoxazole (clearance values with respect to unbound concentration values) appears to be unaltered for the cirrhotic patients. For patients with alcoholic cirrhosis having normal renal function for age and weight, the renal elimination of sulfisoxazole was normal For those subjects with decreased renal function, the renal clearance of sulfisoxazole appeared to be disproportionately decreased, as evidenced by a lower-than-normal sulfisoxazole renal clearance-to-creatinine clearance values. The apparent steady-state volume of distribution of unbound sulfisoxazole was not altered in cirrhotic patients when compared to normal subjects, while the apparent volume of distribution of total drug increased by more than what could be expected from protein binding changes alone. The elimination rate constant did not differ from values found in normals. These data suggest that the total binding capacity of sulfisoxazole in cirrhotic patients is not different from that of normal subjects.
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  • 189
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    Acta neuropathologica 67 (1985), S. 170-173 
    ISSN: 1432-0533
    Keywords: Ethanol ; Rat ; Parietal cortex ; Nuclear inclusions ; Metabolism
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Wistar rats with an average initial body weight of 180 g received a 15% (v/v) ethanol-water solution over a period of 6 months. Neurons of the parietal cortex (area 3) showed a significant increase of nuclear inclusions which consisted of parallel filaments and tubular systems. Furthermore, we observed and augmentation of lipid droplets, nemetosomes, and straight filaments. The latter could not be identified in control animals. It is discussed whether the occurrence of these structures might be enhanced by an altered cellular metabolic activity during the chronic ethanol administration.
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  • 190
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    Acta neuropathologica 67 (1985), S. 13-24 
    ISSN: 1432-0533
    Keywords: Hypoglycemia ; Cerebral cortex ; Nerve cell injury ; Dark neurons ; Acidophilic neurons ; Mitochondria ; Golgi apparatus ; Cell necrosis ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary In the course of a study on the pathogenesis of neuronal necrosis in severe hypoglycemia, the morphological characteristics reflecting reversible and irreversible neuronal lesions were examined as a function of time following normalization of blood glucose. To that end, closely spaced time intervals were studied in the rat cerebral cortex before, during, and up to 1 year after standardized pure hypoglycemic insults of 30 and 60 min of cerebral isoelectricity. Both the superficial and deep layers of the cerebral cortex showed dark and light neurons during and several hours after the insult. By electron microscopy (EM) the dark neurons were characterized by marked condensation of both karyoplasma and cytoplasm, with discernible, tightly packed cytoplasmic organelles. The light neurons displayed clustering of normal organelles around the nucleus with clearing of the peripheral cytoplasm. Some cells, both dark neurons and neurons of normal electron density, contained swollen mitochondrial with fractured cristae. Light neurons disappeared from the cerebral cortex by 4 h of recovery. Some dark neurons in the superficial cortex and almost all in the deep cortex evolved through transitional forms into normal neurons by 6 h recovery. Another portion of the dark neurons in the superficial cortex became acidophilic between 4 and 12 h, and by EM they demonstrated karyorrhexis with stippled electron-dense chromatin. The plasma membrane was disrupted, the cytoplasm was composed of amorphous granular debris, and the mitochondria contained flocculent densities. These definitive indices of irreversible neuronal damage were seen as early as 4–8 h recovery. Subsequently, the acidophilic neurons were removed from the tissue, and gliosis ensued. Thus, even markedly hyperchromatic “dark” neurons are compatible with survival of the cell, as are neurons with conspicuous mitochondrial swelling. Definite nerve cell death is verified as the appearance of acidophilic neurons at which stage extensive damage to mitochondria is already seen in the form of flocculent densities, and cell membranes are ruptured. Our previous results have shown that hypoglycemic neocortical damage affects the superficial laminae, chiefly layer 2. The present results demonstrate that, following the primary insult, this damage evolves relatively rapidly within the first 4–12 h. We have obtained no evidence that additional necrotic neurons are recruited after longer recovery periods.
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  • 191
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    Acta neuropathologica 67 (1985), S. 37-50 
    ISSN: 1432-0533
    Keywords: Hypoglycemia ; Cerebral damage ; Dark neurons ; Neuronal necrosis ; Caudate ; Putamen ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The caudate nucleus and putamen belong to the selectively vulnerable brain regions which incur neuronal damage in clinical and experimental settings of both hypoglycemia and ischemia. We have previously documented the density and distribution of the hypoglycemic damage in rat caudoputamen, but the evolution of the injury, i.e., the sequence of structural changes, has not been assessed. Therefore, in the present study we analyze the light and electron microscopic alterations in the caudoputamen of rats exposed to standardized, pure insults of severe hypoglycemia with isoelectric EEG for 10–60 min, or in rats which, following insults of 30 or 60 min, were allowed to recover for periods from 5 min to 6 months. The hypoglycemic insult produced severe nerve cell injury in the dorsolateral caudoputamen. Immediately after the insult abnormal light neurons with clearing of the peripheral cytoplasm were present. These cells disappeared early in the receovery period, as they do in the cerebral cortex. Dark neurons were also present, but unlike those in the cerebral cortex they did not appear until recovery was instituted. Their number increased for a couple of hours and they became acidophilic within 4–6 h. At this stage, electron microscopy revealed severe clumping of the nuclear chromatin and cytoplasm as well as incipient fragmentation of cell membranes, all these changes indicating an irreversible injury. Within 24 h flocculent densities appeared in the mitochondria and by day 2–3 of recovery the great majority of the medium-sized neurons had undergone karyorrhexis and cytorrhexis, their remnants being subsequently removed by macrophages. After some weeks only large and a few medium-sized neurons remained amidst reactive astrocytes and numerous macrophages. The delay in the appearance of dark, lethally injured medium-sized neurons until the recovery was instituted suggests an effect that does not become apparent until the substrate supply and energy production are restored. Furthermore, it pointt out again the selectivity of the hypoglycemic nerve cell injury with respect to the type (metabolic characteristics?) and topographic location of the neurons.
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  • 192
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    Experimental brain research 60 (1985), S. 501-508 
    ISSN: 1432-1106
    Keywords: Medial terminal accessory optic nucleus ; Rat ; Rabbit and cat ; Neuron morphology ; Dendritic architecture ; Golgi impregnation methods
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The neurons of the medial terminal nucleus (MTN) of the accessory optic system (AOS) have been studied in the rat, rabbit and cat in Golgi-Cox and Golgi-Kopsch impregnated brain sections. The present anatomical findings permit a division of the MTN of these species into dorsal and ventral components (MTNd, MTNv), in agreement with other investigations. The MTNd contains predominantly linear-bipolar and linear-multipolar shaped neurons with cell bodies that measure in the range of 25–50 μm. These neurons have 2 to 4 primary dendrites which, along with their smaller dendritic branches, are oriented in the plane of the long axis of the MTN (i.e. from ventromedial to dorsolateral). These linear-bipolar and linear-multipolar cells represent 70–80% of the neurons of the MTNd as seen in the Golgi impregnated sections. The remaining 20–30% of the MTNd neurons are nearly all multipolar in shape with somata measuring in the range of 15–25 μm. An occasional multipolar neuron is larger, has a soma that measures around 30–60 μm and has dendrites which extend outward from the cell body to cover large areas of the MTNd. There was considerable extension of the dendrites of MTNd neurons into the MTNv; however, the dendrites of MTNd neurons were not observed extending into the adjacent substantia nigra (SN) or ventral tegmental area (VTA) of Tsai (1925). Conversely, the dendrites of neurons in the neighboring SN and VTA course along the borders of the MTN but only occasionally extend into the MTN. The neuron population of the MTNv consists almost entirely of small-multipolar shaped cells with somata measuring from 15–25 μm and dendritic trees resembling those described for multipolar cells of the MTNd. A small number of neurons of the ventral division are medium-multipolar in shape with cell bodies that measure approximately 30–60 μm. Typically, these cells have several dendrites which extend ventrally within the MTNv and one or more dendrites that extend either across the MTNv or dorsally into the MTNd. Only a few linear-bipolar and linear-multipolar neurons were observed in the MTNv. The present findings are discussed in relation to anatomical, physiological, and histochemical studies on the MTN.
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  • 193
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    Experimental brain research 60 (1985), S. 564-575 
    ISSN: 1432-1106
    Keywords: Dorsal lateral geniculate nucleus ; Lateroposterior thalamic nucleus ; Superior colliculus ; Microphthalmia ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Tecto-thalamic projections in the hereditary bilaterally microphthalmic rat were studied by means of WGA-HRP injection into the dorsal lateral geniculate nucleus (LGNd) and the lateroposterior thalamic nucleus (LP). Histological study in the mutant rats showed that whereas LGNd and superficial layers of the superior colliculus (SC) suffered from a remarkable reduction in size, LP had no histological changes as compared to the normal animals. Unilateral injection of the tracer into the microphthalmic LGNd showed that WGA-HRP positive neurons were present mostly in the ipsilateral str. griseum superficiale (SGS) of the SC. However, the number of labeled SGS neurons of the microphthalmic animals was about 3% of the normal. Although cell bodies of the normal tecto-LGNd neurons in the SGS were spindle-form in shape and issued one or two proximal dendrites from each pole, the microphthalmic tecto-LGNd neurons showed an irregular contour and their dendrites were not so intensively labeled. Unilateral injections of WGA-HRP into the LP revealed that the tecto-LP neurons were mainly distributed in the ipsilateral str. opticum of the colliculus. (SO) in both normal and microphthalmic animals. However, the number of labeled SO cells in the microphthalmic rat was about one-half of the normal. Furthermore, the size of labeled tecto-LP neurons was smaller than that of the normal ones, and they showed irregular round to oval cell bodies with equivocally labeled dendrites, in contrast to the normal tecto-LP neurons with polygonal cell bodies extending three or more dendrites in a radial fashion. These results indicate that there exist the tecto-LGNd and -LP projection neurons in the microphthalmic rat and that their laminally segregated projection is fundamentally preserved. However, the number of the tecto-thalamic projection neurons, especially of the tecto-LGNd cells, was markedly diminished in the mutant tectum compared to normals.
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  • 194
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    Bulletin of experimental biology and medicine 100 (1985), S. 1558-1560 
    ISSN: 1573-8221
    Keywords: phosphocreatine ; pharmacokinetics ; man ; experimental animals ; intravenous infusion
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
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  • 195
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    Langenbeck's archives of surgery 366 (1985), S. 715-715 
    ISSN: 1435-2451
    Keywords: Transplantation ; Pancreas ; Rat ; Technique ; Transplantation ; Pankreas ; Ratte ; Techniken
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Zusammenfassung Die Dauer endokriner Funktion allogener Pankreastransplantate mit unterschiedlicher Inselzellmenge and verschiedener Behandlung der exokrinen Sekretion wurde bei jeweils gleicher immunogenetischer Differenz untersucht. Die Dauer der „Abstoßungsreaktion”, besonders nach kurzfrisfger Immunsuppression mit Cyclosporin A, ist von beiden technischen Parametem abhängig. Bei gleicher Inselzellmasse funktionieren sekretdrainierte Transplantate hanger als gangligierte, bei gleicher Behandlung der exokrinen Sekretion verlängert vergrößerte Inselzellmasse die Funktion.
    Notes: Summary The duration of endocrine function of allogeneic pancreatic grafts, with varying amounts of islets and different management of exocrine secretion, was investigated under constant immunological conditions. The duration of the “rejection”, in particular after short-term immunsuppression with cyclosporin, is dependant on both technical variables. With the same mass of islets, secretion-drained grafts function longer than duct-(gated grafts. If the management of exocrine secretion is the same, the duration of endocrine function is prolonged by an increase in the mass of islets.
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  • 196
    ISSN: 1434-0879
    Keywords: PUVA ; Kidney transplantation ; Rat ; UV irradiation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Pretreatment of the kidney donor with 8-methoxypsoralen (8-MOP) and ex vivo longwave ultraviolet irradiation (UVA) of the kidney prolonged the subsequent survival on allogeneic recipients. The efficacy of this treatment seems to be dependent on the time and dose of UVA irradiation rather than on the dose of 8-MOP. In conclusion, PUVA treatment is effective in reducing the immunogenicity of the rat kidney allograft, although the mechanism remains unclear. These experimental findings are new and preliminary results in clinical human kidney transplantation are favourable.
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  • 197
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    Research in experimental medicine 185 (1985), S. 173-179 
    ISSN: 1433-8580
    Keywords: Biliary sepsis ; 125I-labeledE. coli ; Retrograde intrabiliary injection ; Biliary obstruction ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary 125I-labeledE. coli was injected into the biliary tree of normal rats and rats with 3 weeks' obstruction of the common bile duct to investigate the liver clearance capacity for bacteria. Bile was collected during 15 min, immediately, 1h, 4h, or 24h after the injection. Tissue specimens from the liver, lungs, spleen and kidneys, and blood and urine specimens were collected simultaneously. In normal rats, 40% of the bacteria was recovered in the bile immediately after the injection, whereas 30% was already trapped in the liver. Incubation of the bacteria in the bile duct for 1h, 4h, and 24h resulted in liver retentions of 43%, 15%, and 4%, respectively. The recovery in the bile was 13% after 1-h incubation, and further prolongation of the incubation did not result in a significant decrease. In contrast to these findings, 70% of the injected bacteria was retained in the biliary tree in rats with chronic biliary obstruction (P 〈 0.05 as compared to normal rats) and only 1% was trapped in the liver (P 〈 0.005) 15 min after injection. One-hour incubation of bacteria in the bile duct decreased the retention in the bile to 30%, but the retention in the liver increased only slightly in these animals. Four and 24h after injection less than 30% of the bacteria was retained in the hepato-biliary system. Most of these animals showed almost no radioactivity exceeding the background count in the blood, urine, spleen, lungs, and kidneys 15 min after injection. It was concluded that the impaired clearance capacity of the liver in chronic biliary obstruction might contribute to the susceptibility of such animals for bacteria introduced in the bile.
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  • 198
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    European journal of applied physiology 54 (1985), S. 24-29 
    ISSN: 1439-6327
    Keywords: Diaphragm ; Capillary supply ; Fiber type composition ; Growth ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The effect of growth on the capillarity and fiber type composition of the diaphragm, soleus and extensor digitorum longus (EDL) muscles of rats weighing between 55 and 330 g have been studied. Muscle samples obtained from the anesthetized rat were rapidly frozen and sliced transversely in a cryostat. The sections were stained histochemically by the SDH method and the myosin ATPase method after preincubation at pH 4.3 to typify fibers (FG, FOG and SO fibers). To visualize capillaries, the myosin ATPase method after preincubation at pH 4.0 was used. The percentage of FOG fibers decreased in all muscles with growth. While the FG and SO fibers increased in the diaphragm, SO fibers increased in the soleus, and FG fibers increased in the EDL. The capillary density showed a hyperbolic decrease with growth in all muscles, while the number of capillaries around each fiber increased in all muscles with growth. It is concluded that growth causes the changing properties of the motoneurons and the new capillary formation in the diaphragm muscle, as well as the soleus and EDL muscles.
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  • 199
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    European journal of applied physiology 54 (1985), S. 432-435 
    ISSN: 1439-6327
    Keywords: The diaphragm muscle ; The intercostal muscles ; Resistance breathing ; Glycogen ; Triglycerides ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The effect of increased respiratory resistance (stenosis of the trachea) on glycogen and triglyceride levels in the diaphragm (D) and intercostal (external-IE, internal-II) muscles was studied in the rat. Tracheal stenosis resulted in a reduction of glycogen level in the muscles. For the fed rats the reductions were: D-45 and 79%, IE-14 and 30%, II-14 and 35%, 0.5 and 3 h after stenosis, respectively. For rats fasted for 24 h the reductions were: D-64 and 86%, IE-33 and 71%, II-40 and 82%, after 0.5 and 3 h respectively. The level of triglycerides in the muscles was stable during stenosis in the fed group, whereas in the fasted group it were reduced in the diaphragm by 50% after 0.5 h, and by 52% after 3 h. It is concluded that both endogenous and blood-born energy fuels are utilized by the respiratory muscles during increased resistance breathing.
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  • 200
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    Cell & tissue research 239 (1985), S. 3-8 
    ISSN: 1432-0878
    Keywords: GnRH receptors ; Gonadotropes ; Coated pits ; Internalization ; High-resolution autoradiography ; LHRH, Gonadoliberin ; Pituitary gland ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Summary Localization of GnRH receptors in rat pituitary gonadotropes was studied by use of 125I-[azidobenzoyl-D-Lys6]GnRH which, upon photolysis, is covalently bound to the receptor molecule. Using high resolution autoradiography, it was found that, after a 90-min incubation of the analog with pituitary cells at 4° C, 93% of the silver grains were associated with the plasma membrane of the gonadotropes. After 45-min incubation of the cells at 37° C, clustering and internalization of the receptor-bound GnRH analog were evident. Silver grains were associated with coated pits, intracellular vesicles, Golgi complexes, lysosome-like structures and secretory granules. The data indicate that receptor-bound GnRH agonist is internalized, at least in part, via coated pits and is subsequently routed to lysosomes where degradation of the hormone-receptor complex may occur. The presence of a considerable amount of silver grains associated with secretory granules may suggest that some of the internalized receptor molecules can escape degradation and be recycled to the cell membrane.
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