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  • 1980-1984  (34,722)
  • Chemistry  (33,681)
  • Rat  (616)
  • pharmacokinetics  (424)
  • Nuclear reactions
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  • 101
    Electronic Resource
    Electronic Resource
    D-propoxyphene kinetics in man: Significance of a deep third compartment (1984)
    Springer
    European journal of clinical pharmacology 26 (1984), S. 749-752 
    Details
    ISSN: 1432-1041
    Keywords: dextropropoxyphene ; pharmacokinetics ; half-life ; 3-compartment model ; steady state prediction ; plasma levels
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Data from a previously published single dose study of d-propoxyphene 65 mg given i.v. to 8 healthy subjects have been subjected to non linear regression analysis by a curve-fitting program to test the applicability of a 2- and a 3-compartment open model. Analysis of residuals (difference between observed and computed concentrations) revealed similar systematic deviations in all 8 subjects when the 2-compartment model was used (5–10 h negative residuals, after 13 h positive residuals). In contrast, curve-fit by a 3-compartment model (with two parallel peripheral compartments) was good with no systematic deviations. The data show that a terminal monoexponential decline in d-propoxyphene concentrations cannot be expected until 15–30 h after single dose administration, and that the determination of the corresponding half-life is rather inaccurate. Accordingly, precise steady state level predictions may be difficult to obtain from conventional single dose studies with d-propoxyphene.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00541937
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  • 102
    Electronic Resource
    Electronic Resource
    Bioavailability and pharmacokinetics of phenytoin during pregnancy (1984)
    Springer
    European journal of clinical pharmacology 27 (1984), S. 105-110 
    Details
    ISSN: 1432-1041
    Keywords: phenytoin ; epileptic women ; pharmacokinetics ; bioavailability ; pregnancy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Five epileptic women needing to commence phenytoin therapy during pregnancy received a single intravenous and a single oral dose of phenytoin several days apart before starting regular intake of the drug. Plasma phenytoin concentration — time data were analysed by three different pharmacokinetic techniques. However assessed, the mean oral bioavailability of the drug proved to be about 90% of the intravenous bioavailability. This finding makes it unlikely that impaired bioavailability accounts for the increase in oral phenytoin dosage necessary in pregnancy to maintain plasma phenytoin concentrations at pre-pregnancy values. Phenytoin clearance in the pregnant subjects was approximately double the published values for phenytoin clearance in nonpregnant persons. This suggests that increased (metabolic) clearance accounts for the increased phenytoin dosage requirement of pregnancy.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02395215
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  • 103
    Electronic Resource
    Electronic Resource
    Clinical pharmacological studies with the vasodilator endralazine in patients with renal impairment (1984)
    Springer
    European journal of clinical pharmacology 27 (1984), S. 159-163 
    Details
    ISSN: 1432-1041
    Keywords: endralazine ; renal impairment ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The influence of renal impairment on the pharmacokinetics of endralazine was studied in 12 patients; 4 patients on regular haemodialysis therapy (creatinine clearance less than 5 ml/min) and 8 patients with varying degrees of renal impairment (creatinine clearance 11–52 ml/min). Following an oral dose of 10 mg endralazine the mean terminal elimination half-life (βt1/2) in the dialysis sub-group was prolonged at 7.1 h (range 3.3 to 14 h), compared to 3.6 h in the other renal patients (and compared to 2.3 h in hypertensive patients with normal renal function). After one week's therapy with 10 mg B.D. endralazine in the 8 patients with moderate renal impairment there was a significant increase in βt1/2 to 8.6 h but there was no significant change in the area under the drug concentration-time curve and no evidence of drug accumulation. In this study those patients with the poorest renal function had the longest βt1/2 after acute dosing. There was a significant correlation between creatinine clearance and acute βt1/2 but there was considerable variability in individual patients and, even with severe degrees of renal impairment, major dose adjustments do not appear necessary.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00544039
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  • 104
    Electronic Resource
    Electronic Resource
    Pharmacokinetics of a fixed combination of sotalol and hydrochlorothiazide in hypertensive patients with moderate renal insufficiency (1984)
    Springer
    European journal of clinical pharmacology 27 (1984), S. 361-362 
    Details
    ISSN: 1432-1041
    Keywords: sotalol ; hydrochlorothiazide ; pharmacokinetics ; moderate renal failure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Decreased elimination of a combined formulation of Sotalol (160 mg) and hydrochlorothiazide (25 mg) was found in patients with moderate renal insufficiency. Very slight accumulation of sotalol and hydrochlorothiazide was observed, so it appears unnecessary to reduce the dosage in patients with a creatinine clearance of 30 ml/min or more.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00542176
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  • 105
    Electronic Resource
    Electronic Resource
    Pharmacokinetics of propranolol during pregnancy (1984)
    Springer
    European journal of clinical pharmacology 27 (1984), S. 583-587 
    Details
    ISSN: 1432-1041
    Keywords: propranolol ; pregnancy ; beta-adrenoceptor antagonist ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Propranolol, a beta-adrenoceptor blocking drug, was administered to 6 healthy pregnant volunteers between 32 and 36 weeks gestation and when at least 6 weeks postparum. On both occasions, subjects were given propranolol 120 mg orally or 10 mg intravenously in randomised order with a minimum washout period of 1 week. Propranolol was assayed in plasma by gas-liquid chromatography with electron-capture detection and the pharmacokinetic parameters were investigated. There were no significant alterations in elimination half-life, clearance or apparent volume of distribution per kilogram antenatally compared with postnatally: bioavailability was also unchanged. It is concluded that the disposition of propranolol is not altered during pregnancy.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00556896
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  • 106
    Electronic Resource
    Electronic Resource
    Pharmacokinetics of the oral narcotic analgesic bezitramide and preliminary observations on its effect on experimentally induced pain (1984)
    Springer
    European journal of clinical pharmacology 27 (1984), S. 615-618 
    Details
    ISSN: 1432-1041
    Keywords: Bezitramide ; oral absorption profile ; pharmacokinetics ; male volunteers ; experimental pain ; biliary excretion in rats
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The oral absorption of bezitramide 5 mg was studied in 7 human volunteers, using a specific radioimmuno-assay which measured both bezitramide and its active metabolite R-4618. A lag time of 0.5–1.0 h and a Cmax of 5.4 ng/ml plasma were found, the latter occurring 2.5–3.5 h after administration. The apparent elimination half-life varied from 11 to 24 h. Less than 0.3% of the dose was excreted unchanged in the urine. High concentrations in the faeces of some individuals indicate incomplete absorption and/or biliary secretion. The analgesic effect, using a standardized superficial electrical stimulation method, reached its maximum between 2.5 and 3.5 h after dosing, in accordance with the absorption phase. The duration of the effect was highly variable. Experiments in rats (n=6,3H-bezitramide 2.5 µg), demonstrated extensive biliary excretion (up to 70% of total radioactivity) and less than 3% of the label was removed by urinary excretion.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00556902
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  • 107
    Electronic Resource
    Electronic Resource
    Pharmacokinetics of cimetidine in critically ill patients (1984)
    Springer
    European journal of clinical pharmacology 26 (1984), S. 341-346 
    Details
    ISSN: 1432-1041
    Keywords: cimetidine ; pharmacokinetics ; critically ill patients ; intravenous administration ; dose individualization
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Cimetidine disposition was studied after rapid (1 min) intravenous infusion in eight critically ill patients aged between 20 years and 77 years; one patient was studied on two occasions. Cimetidine dose was 300 mg in seven patients and 400 mg in the remaining patient. Arterial plasma cimetidine concentrations at the end of the infusion were very high and ranged from approximately 15–35 mg/l. Pharmacokinetic parameters displayed wide interpatient variability (coefficients of variation of 30–50%) and significant relationships emerged between some of these parameters and certain patient characteristics. Most notable, total systemic plasma clearance of cimetidine was directly related to estimated creatinine clearance (p〈0.01). This relationship might prove to be a useful method of individualizing cimetidine dosage in critically ill patients.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00548765
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  • 108
    Electronic Resource
    Electronic Resource
    Effect of liver failure on the pharmacokinetics of cyclophosphamide (1984)
    Springer
    European journal of clinical pharmacology 26 (1984), S. 591-593 
    Details
    ISSN: 1432-1041
    Keywords: cyclophosphamide ; liver failure ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of cyclophosphamide was investigated in 7 patients in severe liver failure. The pharmacokinetic data were compared with those derived from a matched control group of patients with normal liver function. The half-life (t1/2) of cyclophosphamide following intravenous administration in patients with liver failure was 12.5±1.0 h (m±SD), which was significantly longer than in the normal controls in whom it was 7.6±1.4 h (p〈0.001). The mean total body clearance (Clt) was significantly smaller in liver failure at 44.8+8.6l·kg−1 than in the controls in whom it was 63.0±7.6l·kg−1 (p〈0.01). It is concluded that severe liver disease has a significant effect on the disposition of cyclophosphamide, and that it could lead to accumulation of the drug in the body.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00543491
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  • 109
    Electronic Resource
    Electronic Resource
    Intrapatient variation in tobramycin kinetics in low birth weight infants during first postnatal week (1984)
    Springer
    European journal of clinical pharmacology 26 (1984), S. 647-649 
    Details
    ISSN: 1432-1041
    Keywords: tobramycin ; newborn infants ; intrapatient variations ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Nineteen newborn infants receiving tobramycin, 2.5 mg/kg every 12 h were studied on two occasions at steady-state during the first week of postnatal age. The two studies were separated by two to four days. Total body clearance of tobramycin averaged 1.15 and 1.14 ml/min/kg (p〉0.05), apparent volume of distribution averaged 0.82 and 0.68 l/kg (p〉0.05), and elimination half-life averaged 8.6 and 7.1 h (p〉0.05), during the first and second study, respectively. When the data were further analyzed based on the birth weight, tobramycin kinetics changed during the second study compared to the first study in very low birth weight infants. In eight infants ⩽1.5 kg birth weight, although total clearance of tobramycin was similar, the average apparent volume of distribution decreased from 1.04 l/kg during the first study to 0.73 l/kg during the second study (p〈0.05) and elimination half-life from 11.1 h during the first study to 8.7 h during the second study (p〈0.05). These data indicate that these infants may require a change in dosing interval with continued tobramycin therapy during the first week of postnatal age. Intrapatient variation in tobramycin kinetics should be considered, in addition to the interpatient variation reported previously, when monitoring the serum concentration to individualize tobramycin therapy in newborn infants ⩽1.5 kg birth weight.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00543504
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  • 110
    Electronic Resource
    Electronic Resource
    Acetaminophen accumulation in pediatric patients after repeated therapeutic doses (1984)
    Springer
    European journal of clinical pharmacology 27 (1984), S. 57-59 
    Details
    ISSN: 1432-1041
    Keywords: acetaminophen ; pediatric patients ; fever therapy ; accumulation ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Acetaminophen serum concentrations were studied in 21 infants and children with fever. The maximum serum concentrations ranged from 9.96 to 19.6 µg/ml after a single dose of 12–14 mg/kg and 13.9 to 40.1 µg/ml after a single dose of 22–27 mg/kg. Ten patients were restudied at steadystate after repeat doses had been given every 4 or 8 h for 1 to 3 days. Total area under the acetaminophen serum concentration-time curve normalized for dose averaged 0.181 (ml/min/kg)−1 after the first dose and 0.202 (ml/min/kg)−1 at steady-state (p〈0.05). Five patients showed a 13 to 44% increase in the AUC; one had a 10% decrease in the AUC; and four had less than 6% change in the AUC. There was no evidence of hepatotoxicity. These data suggest that acetaminophen may accumulate after repeated therapeutic doses in children with fever.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02395207
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  • 111
    Electronic Resource
    Electronic Resource
    Effect of food on pharmacokinetics of chlorambucil and its main metabolite, phenylacetic acid mustard (1984)
    Springer
    European journal of clinical pharmacology 27 (1984), S. 111-114 
    Details
    ISSN: 1432-1041
    Keywords: chlorambucil ; chronic lymphocytic leukaemia ; phenylacetic acid mustard ; food intake ; pharmacokinetics ; bioavailability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The influence of food intake on the pharmacokinetics of chlorambucil (C) and its cytotoxic metabolite, phenylacetic acid mustard (PAM), has been studied in man after oral doses of chlorambucil. The administration of chlorambucil with food resulted in slower absorption than when fasting. However, the area under the plasma concentration-time curve (AUC) was unaffected. The mean ratio AUCPAM/AUCC was 2.8 (range 1.4–7.1) under fasting and 3.3 (range 1.3–7.4) under nonfasting conditions. The metabolite very probably plays an important role in the cytotoxic effects observed after administration of C, since calculations show that a major fraction of the metabolite is eliminated by alkylation reactions.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00553164
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  • 112
    Electronic Resource
    Electronic Resource
    Pharmacokinetics of the selective benzodiazepine antagonist Ro 15-1788 in man (1984)
    Springer
    European journal of clinical pharmacology 27 (1984), S. 115-117 
    Details
    ISSN: 1432-1041
    Keywords: benzodiazepine antagonist ; Ro 15-1788 ; healthy volunteers ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of the selective benzodiazepine antagonist Ro 15-1788 has been studied in 6 healthy male volunteers following a single intravenous dose of 2.5 mg. The drug was only slightly bound to plasma proteins (40±8%, mean±SD). A negligible amount (〈0.2% of the dose) of unchanged drug was recovered in urine. Hepatic elimination was rapid, as shown by a short t1/2 of 0.9±0.2 h, and high total plasma and blood clearances of 691±216 ml/min and 716±199 ml/min, respectively. The fast decline of plasma levels from about 60 to 2 ng/ml accounts for the short-lasting reversal of benzodiazepine-induced sedation by Ro 15-1788.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00553165
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  • 113
    Electronic Resource
    Electronic Resource
    Absorption of enprofylline from the gastrointestinal tract in healthy subjects (1984)
    Springer
    European journal of clinical pharmacology 27 (1984), S. 329-333 
    Details
    ISSN: 1432-1041
    Keywords: enprofylline ; healthy subjects ; absorption ; pharmacokinetics ; oral- ; duodenal- ; colonic administration
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Enprofylline, a new potent bronchodilator xanthine drug, was given orally as an aqueous solution to 6 healthy subjects in single doses of 2, 4 and 6 mg/kg. The two lower doses produced plasma concentrations in the range 1–4 mg/l, i.e. in the assumed “therapeutic interval” according to previous animal studies. A high 24 h urine recovery of unchanged drug, with mean values for the three dose levels ranging from 85 to 91% of the given dose, indicated good absorption and little metabolism. The dose-corrected area under the plasma concentration-time curve rose with dose as the latter was increased from 2 to 6 mg/kg. This indicates that the elimination of enprofylline is capacity-limited at high doses. Double peaks in the plasma concentration-time curves at the higher dose levels suggested intermittent and delayed gastric emptying as a possible explanation. This hypothesis was confirmed by studies in 6 other healthy subjects, who received the drug solution by three different routes; by mouth, via a catheter in the duodenum, and rectally via a catheter in the colon. The corresponding time to peak values (mean±SEM) were 32.5±8.7, 13.3±2.5, and 157±23 min.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00542170
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  • 114
    Electronic Resource
    Electronic Resource
    Pharmacokinetic study of the new sulfamethopyrazine-trimethoprim combination (kelfiprim) in renal insufficiency (1984)
    Springer
    European journal of clinical pharmacology 27 (1984), S. 345-348 
    Details
    ISSN: 1432-1041
    Keywords: kelfiprim ; trimethoprim combination ; sulfamethopyrazine combination ; pharmacokinetics ; renal insufficiency
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The combination of trimethoprim (TMP) and sulfamethopyrazine (SMP) has been successfully used to treat chronic urinary tract infections. Since parenchymal involvement associated with renal insufficiency of varying degree is not infrequent in these patients, it was considered important to study the pharmacokinetics of TMP and SMP in a fixed dose combination. Four groups of patients were studied: 1) 4 patients with endogenous creatinine clearance (CLcR) between 80 and 40 ml/min; 2) 3 patients with CLcR between 40 and 10 ml/min; 3) 3 patients on chronic peritoneal dialysis (CAPD); and 4) 3 patients on haemodialysis. A single oral dose of 250 mg TMP and 200 mg SMP was given to each patient. Multiple samples were collected over 9 days and the following pharmacokinetic parameters were calculated: total area under the plasma level curve, slow disposition rate constant β and the corresponding t1/2β, plasma clearance and the apparent volume of distribution. The results show that the two moieties of the TMP-SMP combination behaved differently in uraemic patients as fas as elimination rate was concerned. TMP was eliminated more slowly both in patients with diminished renal function and in those subjected to haemo- or peritoneal dialysis. The reduction in the rate of elimination of TMP was significantly correlated with the degree of renal impairment. The elimination of SMP, however, was not significantly affected by the reduced renal function; indeed a tendency to increase was noted, at least in dialyzed patients. However, as in patients with mild renal insufficiency (CLcR〉40 ml/min) no substantial change in plasma clearance rate need be expected, the TMP-SMP combination could be given to them in the same dose schedule as in people with normal renal function.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00542173
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  • 115
    Electronic Resource
    Electronic Resource
    Pharmacokinetics of canrenone and metabolites after base hydrolysis following single and multiple dose oral administration of spironolactone (1984)
    Springer
    European journal of clinical pharmacology 27 (1984), S. 441-446 
    Details
    ISSN: 1432-1041
    Keywords: spironolactone ; canrenone ; metabolites ; pharmacokinetics ; single/multiple oral doses ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of canrenone and ‘total metabolites’ after base hydrolysis was studied in eight young volunteers following single and multiple dose oral administration of spironolactone. The plasma levels of canrenone and ‘total metabolites’ were fitted to a two-compartment open model with a first-order absorption process. From our eight normal subjects studied, the harmonic mean of the distributive half-life (t1/2α) of canrenone was found to be 1.66 h, and the harmonic mean of the terminal elimination half-life (t1/2β) to be 22.6 h. Harmonic means of the distributive and elimination half-lives of ‘total metabolites’ after base hydrolysis were 2.48 h and 28.8 h respectively. The accumulation ratio of canrenone was 2.53, whereas that of ‘total metabolites’ was 1.89. Despite the fact that spironolactone has been shown to induce hepatic metabolism of other drugs, no evidence of autoinduction was noted in the present study, as plasma levels of canrenone and ‘total metabolites’ were found to obey a linear two-compartment model with reproducible absorption and disposition after single and multiple doses.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00549592
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  • 116
    Electronic Resource
    Electronic Resource
    Pharmacokinetics of mepindolol in patients with chronic renal failure (1984)
    Springer
    European journal of clinical pharmacology 27 (1984), S. 429-433 
    Details
    ISSN: 1432-1041
    Keywords: mepindolol ; renal failure ; haemodialysis ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Five patients with a creatinine clearance of 14 to 37 ml/min/1.73 m2 were each given an oral dose of 10 mg of the beta-blocker mepindolol sulphate (Corindolan). In addition, two dialysis patients received the same dose either during hemodialysis or on a dialysis-free day. Plasma levels of mepindolol were measured by a sensitive, specific HPLC method. Mepindolol was rapidly absorbed in all the patients. The maximum plasma level of 35±8 ng/ml was reached after 1.4±0.5 h. The half-life of disposition was 4.0±1.5 h. The area under the plasma concentration-time curve was 237±84 ng × h/ml. The data obtained were no different from those found in normal healthy volunteers.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00549590
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  • 117
    Electronic Resource
    Electronic Resource
    Tolerance and pharmacokinetics of A515U, an acyclovir analogue, in healthy volunteers (1984)
    Springer
    European journal of clinical pharmacology 27 (1984), S. 471-475 
    Details
    ISSN: 1432-1041
    Keywords: acyclovir ; A515U ; 6-deoxyacyclovir ; pharmacokinetics ; prodrug ; antiviral chemotherapy ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary A515U (6-deoxyacyclovir) is an analogue of acyclovir devoid of antiviral activity in vitro but which is well absorbed and undergoes conversion to acyclovir after oral administration to rats. The tolerance and pharmacokinetics of various doses of A515U have been studied in 8 healthy volunteers. Single oral doses of 25, 50, 100, 200 and 400 mg A515U and 400 mg acyclovir for comparison were administered to the volunteers at weekly intervals. Concentrations of the parent drug and acyclovir were determined in plasma and urine. The prodrug was well tolerated and did not cause adverse reactions or changes in haematological or biochemical variables. It was well absorbed and conversion to acyclovir was rapid and extensive at all doses. Plasma concentrations of acyclovir achieved with 50 mg A515U orally were comparable to and less variable than those produced by 400 mg acyclovir. A515U was rapidly cleared with a short plasma elimination half life of approximately 0.5 h. The attainment of high plasma concentrations of acyclovir by oral administration of a prodrug may represent an important advance in antiviral chemotherapy.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00549597
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  • 118
    Electronic Resource
    Electronic Resource
    Biperiden effects and plasma levels in volunteers (1984)
    Springer
    European journal of clinical pharmacology 27 (1984), S. 619-621 
    Details
    ISSN: 1432-1041
    Keywords: biperiden ; pharmacokinetics ; pharmacodynamics ; plasma levels
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of biperiden was studied and compared with pharmacodynamics (pupil size, accomodation, self-rating mood scale) in 6 healthy volunteers. A single-blind cross-over design was employed with placebo and biperiden (4 mg as commercially available tablets). After a lag time of 0.5 h, biperiden was rapidly absorbed with a half-life of 0.3 h, plasma peak levels of 5 ng/ml being reached after 1.5 h. Biperiden showed good tissue penetration (distribution half-life 0.6 h; ratio of total to central distribution volume 9.6), the terminal half-life time of plasma concentration was 18 h, and the oral clearance was 146 l/h. The pharmacodynamic maximum lagged behind the plasma peak concentration by 1 (self-rating) to 4 h (accommodation).
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00556903
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  • 119
    Electronic Resource
    Electronic Resource
    Ultrastructural changes in rat Clara cells induced by a single dose of O,S,S-trimethyl phosphorodithioate (1984)
    Springer
    Archives of toxicology 56 (1984), S. 59-65 
    Details
    ISSN: 1432-0738
    Keywords: Trialkylphosphorothioates ; Rat ; Lung ; Ultrastructure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The oral administration of an LD50 dose (25 mg/kg) of O,S,S-trimethyl phosphorodithioate to rats induced immediate, cholinergic symptoms. A delayed respiratory crisis followed, 3–4 days later, involving a pronounced increase in lung weight and extensive injury to the alveolar epithelium. This compound also induced the immediate liberation of secretory granules from the Clara cells. Minor changes in the surface appearance of these cells were also observed but no signs of injury were found in any cells of the bronchiolar epithelium. The complement of secretory granules was monitored, by the morphometric analysis of ultrathin sections. Clara cells from control animals were found to contain 9.55±1.16 (SEM) granules per cell profile. The Clara cells from dosed animals were largely devoid of granules until the 3rd day after administration. Many of these agranular cells were arranged in clusters and often showed signs of mitotic division. In surviving animals the subsequent replacement of granules resulted in a large increase in the numbers present and many exhibited abnormal morphology. Over twice the normal complement of granules, 22.45±0.42 (SEM) per cell profile, was found 6 days after dosing. The complement of granules subsequently returned to normal levels and the clusters of Clara cells were resolved within 14 days of dosing.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00316355
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  • 120
    Electronic Resource
    Electronic Resource
    Comparison between the effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin and six other compounds on the vitamin A storage, the UDP-glucuronosyltransferase and the aryl hydrocarbon hydroxylase activity in the rat liver (1984)
    Springer
    Archives of toxicology 55 (1984), S. 16-19 
    Details
    ISSN: 1432-0738
    Keywords: TCDD ; 2,3,7,8-Tetrachlorodibenzo-p-dioxin ; 3-Methylcholanthrene ; Phenobarbital ; 2,3,7,8-Tetrabromodibenzo-p-dioxin ; Toxaphene ; 5-Chloro-2-(2,4-dichlorophenoxy)phenol ; 4,5,6-Trichloro-2-(2,4-dichlorophenoxy)phenol ; Vitamin A ; Retinol ; UDP-glucuronosyltransferase ; Aryl hydrocarbon hydroxylase ; Liver ; Rat ; High pressure liquid chromatography
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 2,3,7,8-tetrabromodibenzo-p-dioxin (TBrDD), 5-chloro-2-(2,4-dichlorophenoxy)phenol(3-Cl-predioxin) 4,5,6-trichloro-2-(2,4-dichlorophenoxy)phenol (5-Cl-predioxin), toxaphene, 3-methylcholanthrene (3-MC) and phenobarbital (PB) on the vitamin A storage, UDP-glucuronosyltransferase (UDPGT) and aryl hydrocarbon hydroxylase (AHH) activities in the liver of Sprague-Dawley rats was investigated. Vitamin A was determined as retinol by high pressure liquid chromatography. UDPGT was measured with p-nitrophenol as an aglycone and AHH with 3,4-benzopyrene as a substrate. Both in TCDD- and toxaphene-treated animals a reduced body weight gain was recorded, but no other overt signs of toxicity were seen in this study. Both the concentration and the total amount of hepatic retinol was significantly reduced in TCDD-, 3-MC-, PB- and TBrDD-treated animals. These compounds were also those which gave the most significant enzyme induction as regards the UDPGT and AHH activities. However, the reduction of hepatic retinol caused by these compounds did not correlate with the enzyme activities studied. When compared on a molecular basis, TCDD and TBrDD were in the order of several magnitudes more potent as reducers of hepatic retinol and likewise as enzyme inducers.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00316580
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    Ro 15-1570, a new sulfur-containing retinoid devoid of bone toxicity in rats (1984)
    Springer
    Archives of toxicology 56 (1984), S. 117-122 
    Details
    ISSN: 1432-0738
    Keywords: Rat ; Retinoids ; Bone alterations ; Adverse effects ; Arotinoid ethylsulfone
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Repeated ingestion of high doses of retinoids cause the so-called hypervitaminosis A syndrome. In rats the main symptoms are weight loss, alopecia, erythema, desquamation of the skin, and alterations of the skeletal system, including bone fractures. In the present study, three retinoids (Ro 15-1570, arotinoid ethylsulfone, 6 mg/kg; retinoic acid, 100 mg/kg and etretinate, 50 mg/kg) were administered orally to rats for 1 and 2 weeks, respectively, to six male and six female rats/group. All the above changes were induced by all three retinoids, with the exception that the arotinoid ethylsulfone Ro 15-1570 did not cause bone alterations. The absence of toxic effects on the bones by Ro 15-1570 was confirmed by X-ray-film examinations, densitometry of the X-rayed femora and tibiae, examination of the thickness of the femoral and tibial compacta in histological slides plus the determination of the femoral ash weight and its main inorganic constituents (calcium, magnesium, sodium, and potassium). The present demonstration that the arotinoid ethylsulfone Ro 15-1570 was devoid of bone toxicity constitutes major progress in the pharmacologic development of retinoids with a better balance between therapeutic and adverse effects.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00349083
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  • 122
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    Glucuronidation in rat intestinal epithelial cells (1984)
    Springer
    Archives of toxicology 55 (1984), S. 123-126 
    Details
    ISSN: 1432-0738
    Keywords: Rat ; Intestinal cells ; Glucuronidation ; 1-Naphthol ; Glucose ; Fructose ; d-Galactosamine ; Ethanol ; Diethyl ether ; Sorbitol
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Glucuronidation of 1-naphthol was studied in mucosal cells isolated from the rat intestine. Glucuronidation was directly dependent on the supply of extracellular carbohydrates. Basal glucuronidation (ca. 0.3 nmoles/min · mg cell protein) was increased 2- to 3-fold by adding glucose or fructose to the incubation medium. Saturation of glucuroniation was achieved by adding 0.3 mM glucose, while saturation by fructose was not reached at concentrations below 2 mM. No carbohydrate reserves able to support glucuronidation appear to be present in intestinal cells, since no difference in glucuronidation was observed between cells prepared from fasted (18 or 42 h) and control rats. Glucuronidation was decreased by adding d-galactosamine to the incubation medium, but only when extracellular glucose was present. Various chemicals which are known to inhibit glucuronidation in hepatocytes (ethanol, diethyl ether, sorbitol) did not influence the glucuronidation of 1-naphthol in isolated intestinal cells. Only when ethanol was added to mucosal cells in the absence of extracellular glucose was a small decrease in glucuronidation observed.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00346050
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  • 123
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    Phthalate esters (1984)
    Springer
    Archives of toxicology 55 (1984), S. 132-136 
    Details
    ISSN: 1432-0738
    Keywords: Phthalate esters ; Inhalation ; Rat ; Enzymatic activities
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Male Sprague Dawley rats were exposed to dibutylphthalate (DBP) by inhalation with concentrations of 0.5, 2.5, and 7.0 ppm in the air for 5 days. The concentrations were considered relevant to human exposure. No quantitative changes were observed in liver microsomal cytochrome P-450 related enzymes, but significant increase was observed in the liver microsomal metabolism of benzo(a)pyrene and n-hexane, in the 2.5 ppm and 0.5 ppm groups, respectively. Inhaled DBF decreased in a dose-dependent way the lung microsomal concentration of cytochrome P-450 by as much as 63%, which was reflected in a significant reduction of the microsomal metabolism of n-hexane and benzo(a)pyrene in the 7.0 ppm group. It is concluded that DBP in doses relevant to human air exposure influences the cytochrome P-450 enzyme system in both liver and lung, with lung as the main target organ. The observed effects in lung microsomes were similar to those earlier reported after IP administration of high doses of DBP.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00346052
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  • 124
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    A method of studying the intestinal absorption of aluminium in the rat (1984)
    Springer
    Archives of toxicology 55 (1984), S. 168-172 
    Details
    ISSN: 1432-0738
    Keywords: Aluminium ; Intestinal absorption ; Methodology ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Aluminium (Al) intoxication in dialysis patients is held to be caused not only by Al in the dialysis fluid but also by Al from orally administered phosphate binders. Studies on Al absorption in patients and healthy individuals as well as in animals are still scarce, and do not provide sufficient data to characterize the absorption process. This paper presents a method of studying the process of Al absorption in a perfusion system of rat small intestine in vivo, in combination with a cannulation system of the portal vein for serial blood sampling. Determination of concentrations of an absorbed substance in samples of both the perfusion medium and the portal blood, collected during the perfusion period, may clarify the nature of the absorption process. Although this method appears to be useful for the study of the intestinal absorption of any substance, it was adapted for the study of the intestinal absorption of Al compounds. The usefulness of this method for studying Al absorption was demonstrated in an experiment in which Al chloride (0.5 g/l) in buffered media of pH 7.0, 7.5, and 8.0 was perfused through the rat small intestine over a period of at least 30 min. The results of this experiment indicate that a decrease in pH of the perfusion medium leads to an increase in absorption of Al in the portal blood.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00316122
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  • 125
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    The effect of 2,3-dimercaptopropane sodium sulfonate on mercury retention in rats in relation to age (1984)
    Springer
    Archives of toxicology 55 (1984), S. 250-252 
    Details
    ISSN: 1432-0738
    Keywords: 203Hg ; DMPS ; Age ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The effectiveness of DMPS (sodium 2,3-dimercaptopropane-1-sulfonate) in reducing inorganic mercury retention was studied in 2-, 6-, and 28-week-old albino rats. 203Hg was administered IP. The chelating agent DMPS was administered by IP injection at a dose of 250 μmol/kg body weight three times, 1 day after 203Hg administration and at 24 h intervals thereafter. The whole body retention determined 1, 2, 3, and 6 days after 203Hg administration showed that DMPS decreased the body retention of mercury in all age groups, being about twice as effective in adult compared to suckling rats. The reduced effectiveness was due to the reduced efficacy of DMPS in reducing kidney retention in young animals. In other organs the effectiveness of DMPS was not age dependent. These and previous results obtained with different chelating agents and other metals indicate that age might be an important factor in chelation therapy in general.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00341020
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  • 126
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    In vivo metabolism of dimethylformamide and relationship to toxicity in the male rat (1984)
    Springer
    Archives of toxicology 56 (1984), S. 87-91 
    Details
    ISSN: 1432-0738
    Keywords: Dimethylformamide ; N-Hydroxymethyl-N-methylformamide ; N-Methylformamide ; Metabolism ; Toxicity ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract After in vivo administration of dimethylformamide (DMF) to male rats, about 50% of the dose is excreted in urine as N-hydroxymethyl-N-methylformamide (DMF-OH) and about 4% as N-methylformamide (NMF). NMF is not a product of DMF-OH biotransformation but is directly formed from DMF. Comparison of the acute toxicity of DMF, DMF-OH and NMF shows that NMF is more toxic than DMF-OH, which is itself more toxic than DMF. This study explains the different toxicity profile of DMF and NMF which until recently was believed to represent the main metabolite of DMF.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00349077
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    The toxicity and neuropathology of 2,4,5-tribromoimidazole and its derivatives in rats (1984)
    Springer
    Archives of toxicology 56 (1984), S. 109-112 
    Details
    ISSN: 1432-0738
    Keywords: 2,4,5-Tribromoimidazole ; Rat ; Neuronal necrosis ; Uncoupling of oxidative phosphorylation ; Ataxia
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract 2,4,5-tribromoimidazole and its 1-n-butylcarboxylate and 1-dimethylcarbamoyl derivatives, when administered to rats, induced poisoning typical of uncouplers of oxidative phosphorylation. At 48 h rats surviving a single toxic dose of 20–60 mg/kg developed permanent incoordination of the hindlimbs in the absence of brain oedema. Neuropathologic examination of brain and spinal cord from perfused fixed rats at 24 h revealed neuronal necrosis and chromatolysis in the vestibular nucleus, the outer parietal neocortex and red nucleus. Chromatolysis and necrosis in these areas had increased at 72–96 h and were also observed in the deeper layers of the neocortex, the medial entorhinal cortex, the reticular formation, the grey matter of the spinal cord extending into the ventral horns, the dorsal, and ventral cochlear nuclei and the deep cerebellar nuclei, in decreasing order of severity. Neuronal necrosis was accompanied by an increased glial response, including neuronophagia and at 16 days with astroglial hypertrophy and hyperplasia.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00349081
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  • 128
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    Differences in the distribution of methyl mercury in erythrocytes, plasma, and brain of Japanese quails and rats after a single oral dose (1984)
    Springer
    Archives of toxicology 56 (1984), S. 132-135 
    Details
    ISSN: 1432-0738
    Keywords: Methyl mercury ; Toxicokinetics ; Differential toxicity ; Japanese quail ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Distribution of a single oral dose of methyl mercury (10 mg Hg/kg body weight) was followed from 90 min up to 120 h in plasma, erythrocytes, and brain of Japanese quails and rats. Significantly higher Hg concentrations were observed in plasma and brain of quails and red blood cells of rats. Blood/brain ratio decreased in quails from 6 to 2 at 24 h and 120 h respectively, whereas it increased in rats. Erythrocyte/plasma ratio in quails was about three times lower and averaged 54. The differences in Hg distribution were accompanied by a more than 3-fold higher acute toxicity in quails under adequate experimental conditions.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00349086
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  • 129
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    Pharmacokinetic and pharmacodynamic interaction study of diazepam and metoprolol (1984)
    Springer
    European journal of clinical pharmacology 26 (1984), S. 223-226 
    Details
    ISSN: 1432-1041
    Keywords: diazepam ; metoprolol ; drug combination ; pharmacodynamics ; pharmacokinetics ; drug metabolism ; sedation ; interaction study
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In 6 normotensive, healthy male volunteers the pharmacodynamic responses (blood pressure, heart rate; sedation index, tracking test, reaction time) to metoprolol (100 mg bid orally), diazepam (0.1 mg/kg intravenously) and to their combination were studied. The pharmacokinetics of diazepam were also compared in a cross-over experiment, with and without pretreatment by the β-adrenoceptor antagonist to evaluate the possibility of a drug interaction. The pharmacodynamic and pharmacokinetic investigations indicated that metoprolol only slightly impaired the elimination of diazepam (18% decrease in total clearance, 25% increase in elimination half-life). The pharmacodynamics of metoprolol (17% decrease in heart rate, 17% decrease in diastolic RR) was not significantly altered by the bolus injection of diazepam. The extent of prolongation in choice reaction time (RT2) induced by diazepam was significantly (p=0.001) more pronounced following the co-administration of metoprolol. However, the results of RT1, the tracking test and the sedation index did not indicate any increased effect due to the β-blocking agent. It is concluded that concomitant treatment with metoprolol and diazepam causes only minor and clinically irrelevant changes in drug metabolism and drug response.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00630289
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  • 130
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    Pharmacokinetics of estramustine phosphate (Estracyt®) in prostatic cancer patients (1984)
    Springer
    European journal of clinical pharmacology 26 (1984), S. 113-119 
    Details
    ISSN: 1432-1041
    Keywords: estramustine phosphate ; prostatic cancer ; pharmacokinetics ; metabolism ; estramustine
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of estramustine phosphate (EMP) was studied in five prostatic cancer patients given single i.v. and oral doses of EMP in a cross-over study. Plasma and urinary concentrations of parent drug, estramustine, estromustine (the estrone analogue), estradiol and estrone were followed for 32 h. The elimination of intravenous EMP from plasma was biphasic. The mean volumes of distribution were small, being 43 and 108 ml/kg for the central and peripheral compartments, respectively. The plasma clearance was 64 ml/kg/h, and the half-lives of the two phases were 0.16 and 1.27 h. Metabolism was the major route of elimination of EMP. It was readily dephosphorylated and oxidized to yield the cytotoxic metabolites estramustine and estromustine. Estromustine was the main metabolite in plasma. When given orally EMP underwent extensive presystemic dephosphorylation, which started in the gastrointestinal tract. The relative bioavailability of estromustine after administration of EMP-capsules was 44%, which reflects incomplete absorption of EMP rather than first-pass metabolism of estromustine. The terminal half-life of estromustine was 10–20 h, which suggests that EMP might be given once or twice a day.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00546718
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    Correlation between the pharmacokinetics and pharmacodynamics of dopamine in healthy subjects (1984)
    Springer
    European journal of clinical pharmacology 26 (1984), S. 163-169 
    Details
    ISSN: 1432-1041
    Keywords: dopamine ; pharmacokinetics ; pharmacodynamics ; adrenaline plasma level ; noradrenaline plasma level ; blood pressure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics and the pharmacodynamic action of dopamine were investigated in 5 healthy subjects. Dopamine was given in different doses (200, 400 and 800 µg/min) by constant intravenous infusion over 90 min. In order to control the influence of the procedure on the measured parameters the subjects also received a similar infusion of saline. Dopamine, noradrenaline and adrenaline levels in plasma were followed for up to 6 h after the infusion, and arterial pressure and heart rate were monitored. Dopamine reached a steady state level within 15 to 30 min after commencement of the infusion; the steady state levels averaged 36.5 µg/l at 200 µg/min, 73.8 µg/l at 400 µg/min and 207 µg/l at 800 µg/min. The corresponding total clearances were 5.8 l/ min, 5.51/min and 3.9 l/min suggesting non-linear kinetics. The kinetics could not be described by compartmental model. Noradrenaline and adrenaline levels were found to be elevated during infusion of dopamine. Noradrenaline had returned to its pretreatment level within 15 to 30 min after cessation of the infusion, whereas the adrenaline level did not return to the pretreatment value within the observation period. Heart rate was increased by the dose of 400 µg/min, and the systolic and mean arterial pressures were elevated, whereas distolic blood pressure remained unchanged. Elevated systolic blood pressure was better correlated with plasma dopamine than with noradrenaline concentration. This finding, in conjunction with the unchanged diastolic blood pressure, indicates that elevation of the systolic blood pressure is a direct rather than an indirect effect of dopamine. The increased heart rate was not correlated with the dopamine level.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00630281
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    Bioequivalence studies in humans of indomethacin capsules marketed in India (1984)
    Springer
    European journal of clinical pharmacology 26 (1984), S. 261-264 
    Details
    ISSN: 1432-1041
    Keywords: indomethacin capsules ; bioequivalence ; volunteers ; pharmacokinetics ; statistical significance ; bioavailability ; comparative bioequivalence
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Two, separate 6×6 Latin square cross-over bioequivalence studies were performed in adult male volunteers using 10 different indomethacin capsule preparations marketed in India together with the pure drug powder as the standard. The products were evaluated with respect to plasma level at various times up to 8 h following administration of a 50 mg (2 × 25 mg) dose. Plasma samples were analysed by a fluorimetric method. Various pharmacokinetic parameters were calculated according to a two compartment model. Statistical evaluation of the data employed analysis of variance for a cross-over design (ANOVA) and Duncan's multiple range test to ascertain the significance of differences between the products. Of the 10 products studied, two were found to be bioinequivalent.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00630296
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  • 133
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    Lack of clinically important interaction between erythromycin and theophylline (1984)
    Springer
    European journal of clinical pharmacology 26 (1984), S. 485-489 
    Details
    ISSN: 1432-1041
    Keywords: theophylline ; erythromycin ; interaction ; metabolism ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In 11 healthy volunteers the kinetics of theophylline and the plasma levels and the urinary excretion of its metabolites were studied before and after treatment with erythromycin for 10 days. Theophylline was administered as an intravenous bolus injection (280 mg) followed by a constant intravenous infusion (23.8±4.1 mg/h) for 6 hours. The total clearance of theophylline at steady-state (63.4±9.9 vs 63.8±14.4 ml/min, before vs after erythromycin treatment) and the elimination half-life after cessation of the infusion (6.7±2.6 vs 7.5±1.8 h, before vs after treatment) did not change during the treatment with erythromycin. No difference in the formation of metabolites before and after treatment with erythromycin was detected; the findings in urine were 40.4±5.0 vs 42.1±5.4% 1,3-dimethyluric acid, 29.6±4.6 vs 30.1±5.9% 1-methyluric acid and 13.4±3.5 vs 12.5±2.2% 3-methylxanthine before and after erythromycin treatment, respectively. It is concluded that a clinically relevant interaction between erythromycin and theophylline does not occur.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00542146
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  • 134
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    Single and multiple dose kinetics of clobazam, and clinical effects during multiple dosage (1984)
    Springer
    European journal of clinical pharmacology 26 (1984), S. 499-503 
    Details
    ISSN: 1432-1041
    Keywords: benzodiazepines ; clobazam ; desmethylclobazam ; pharmacokinetics ; sedation ; accumulation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Sixteen healthy volunteers, aged 19 to 62 years, took a single 20-mg oral dose of clobazam and the serum concentrations of clobazam and desmethylclobazam were measured for the following 7 days. The mean kinetic variables for clobazam were: volume of distribution 1.31/kg, elimination half-life 24 h, total clearance 0.47 ml/min/kg. 13 of the volunteers then took clobazam 5 mg twice daily for 22 consecutive days. Serum concentrations were measured during and after this period. Both clobazam and desmethylclobazam showed slow and extensive accumulation, their steady-state kinetics being entirely consistent with those observed after single doses. Elimination of both compounds after termination of treatment was equally slow. Clinical self-rating of morning sedation indicated a significant increase over baseline in subjective perception of sedation during the treatment period, and this effect persisted into the washout period. However, sedation did not increase in parallel with accumulating levels of clobazam and desmethylclobazam, probably due to functional adaptation or tolerance.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00542148
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  • 135
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    Pharmacokinetic interaction of contraceptive steroids with prednisone and prednisolone (1984)
    Springer
    European journal of clinical pharmacology 26 (1984), S. 505-511 
    Details
    ISSN: 1432-1041
    Keywords: prednisolone ; prednisone ; oral contraceptives ; 6β-hydroxylase ; transcortin ; protein-binding ; steroid metabolism ; pharmacokinetics ; drug interaction
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The oestrogenic component of oral contraceptives affects the activity of liver enzymes and the concentrations of plasma proteins implicated in steroid metabolism and transport. The present study was designed to determine these effects on the kinetics of prednisone and prednisolone. After an oral dose of prednisone, women on oral contraceptive steroids (n=10) had higher mean (±SD) area under the plasma concentration versus time curves of total (428±67 µg/ml/min vs 188±28 µg/ml/min, p〈0.001) and unbound prednisolone (64±10 µg/ml/min vs 41±10 µg/ml/min, p〈0.001) than women not taking oral contraceptive steroids (n=10). The differences were attributable to a lower non-renal clearance of prednisolone and to a higher apparent systemic availability of the drug in contraceptive users than in the controls. The affinity of albumin and transcortin for prednisolone was lower in women on oral contraceptives than in controls (p〈0.001). Thus, altered kinetics and protein binding may account for the known increase in glucocorticoid efficacy by oestrogens.
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    URL: http://dx.doi.org/10.1007/BF00542149
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  • 136
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    Acetaminophen accumulation in pediatric patients after repeated therapeutic doses (1984)
    Springer
    European journal of clinical pharmacology 27 (1984), S. 57-59 
    Details
    ISSN: 1432-1041
    Keywords: acetaminophen ; pediatric patients ; fever therapy ; accumulation ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Acetaminophen serum concentrations were studied in 21 infants and children with fever. The maximum serum concentrations ranged from 9.96 to 19.6 µg/ml after a single dose of 12–14 mg/kg and 13.9 to 40.1 µg/ml after a single dose of 22–27 mg/kg. Ten patients were restudied at steadystate after repeat doses had been given every 4 or 8 h for 1 to 3 days. Total area under the acetaminophen serum concentration-time curve normalized for dose averaged 0.181 (ml/min/kg)−1 after the first dose and 0.202 (ml/min/kg)−1 at steady-state (p〈0.05). Five patients showed a 13 to 44% increase in the AUC; one had a 10% decrease in the AUC; and four had less than 6% change in the AUC. There was no evidence of hepatotoxicity. These data suggest that acetaminophen may accumulate after repeated therapeutic doses in children with fever.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00553155
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  • 137
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    Pharmacokinetics of metoprolol in healthy, elderly, non-smoking individuals after a single dose and two weeks of treatment (1984)
    Springer
    European journal of clinical pharmacology 27 (1984), S. 217-222 
    Details
    ISSN: 1432-1041
    Keywords: metoprolol ; pharmacokinetics ; age effect ; repeated doses ; pre-systemic elimination ; total body clearance
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effect of long-term treatment on the absorption and dispsoition of metoprolol has been evaluated in 8 healthy, non-smoking, elderly individuals (mean age 74.5 years) and in a control group of 8 healthy, young individuals. Two trace doses of [3H]metoprolol were given i.v., first concomitantly with a single oral 50 mg dose of cold metoprolol, and second, with the morning dose after 2 weeks of treatment with 50 mg b.d. In the elderly, the mean AUC increased by about 45% (p〈0.05) over the treatment period, while in the control group the mean AUC was 18% greater (p〈0.05) on Day 14 than on Day 1. In the elderly, changes both in pre-systemic elimination and in total body clearance accounted for the elevation of the AUC, whereas reduced first-pass effect appeared to be the major cause of the increased steady-state plasma level in the control group. With the exception of the volume term, V β , the pharmacokinetic parameters were not significantly different between the elderly and the young individuals. For this reason, almost identical steady-state plasma levels were attained in the two groups. The results suggest that age-related physiological changes may have some minor effects on the pharmacokinetics of metoprolol, and also that the changes do not lead to significantly altered plasma concentrations compared to those in young individuals.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00544048
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  • 138
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    Lack of effect of haemodialysis on mebendazole kinetics: Studies in a patient with echinococcosis and renal failure (1984)
    Springer
    European journal of clinical pharmacology 27 (1984), S. 243-245 
    Details
    ISSN: 1432-1041
    Keywords: mebendazole ; haemodialysis ; echinococcosis ; pharmacokinetics ; protein binding
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effect of haemodialysis on mebendazole kinetics has been studied in a patient receiving both mebendazole therapy and haemodialysis. The procedure of haemodialysis did not influence the plasma concentration — time profiles or the mean daily plasma levels. The arterio-venous difference in the dialyser was negligible and no mebendazole could be detected in the dialysate. Protein binding of mebendazole was 90% before dialysis and 88% during dialysis and not significantly different from the binding in patients without renal disease (91.4±1.9%, n=22).
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00544053
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  • 139
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    Electronic Resource
    Naproxen disposition in patients with alcoholic cirrhosis (1984)
    Springer
    European journal of clinical pharmacology 27 (1984), S. 291-296 
    Details
    ISSN: 1432-1041
    Keywords: naproxen ; cirrhosis ; pharmacokinetics ; protein binding ; nonsteroidal antiinflammatory drugs
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Chronic liver disease is known to alter the absorption and disposition of many drugs. To assess the influence of chronic alcoholic liver disease on the disposition of naproxen, we administered the drug both as a single dose and to steady state to 10 individuals with alcoholic cirrhosis and to 10 healthy controls. Plasma and serum samples collected after naproxen dosing were assayed for both total and (following equilibrium dialysis) unbound drug concentration. Clearance calculated based on both total and unbound naproxen concentration revealed no change in total plasma clearance of the drug at steady state but a marked reduction of approximately 60% in clearance based on unbound drug. Naproxen volume of distribution changed only minimally. Because clearance based on unbound drug concentration at a given dosing rate determines the plasma or blood free drug concentration, this concentration may increase significantly in patients with alcoholic liver disease given usual doses of naproxen. Unbound drug concentration is thought to determine the pharmacologic effect of a drug. We therefore recommend that naproxen dosing be reduced by at least half in patients with chronic alcoholic liver disease. In the absence of data to the contrary, this recommendation can be extended to individuals with other forms of hepatic disease.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00542162
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  • 140
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    The pharmacokinetics of a new radiosensitiser, Ro 03-8799 in humans (1984)
    Springer
    European journal of clinical pharmacology 27 (1984), S. 483-489 
    Details
    ISSN: 1432-1041
    Keywords: radiosensitiser ; pharmacokinetics ; healthy volunteers ; tumour patients ; Ro 03-8799
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary A new hypoxic cell radiosensitiser, Ro 03-8799 has been administered intravenously to human volunteers and its kinetic parameters derived from plasma and urine data. Good penetration of drug into tumour tissue is found, consistent with its large volume of distribution. The plasma clearance of this compound is rapid due to high metabolic and renal clearances. These parameters combine to produce an elimination half-life of 5.6 h, approximately half that of misonidazole, a well studied radiosensitiser. It is hoped that this decrease in total body exposure will also reduce the cumulative toxicity seen when misonidazole is administered repeatedly.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00549599
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  • 141
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    Pharmacokinetics of valpromide after oral administration of a solution and a tablet to healthy volunteers (1984)
    Springer
    European journal of clinical pharmacology 27 (1984), S. 501-503 
    Details
    ISSN: 1432-1041
    Keywords: valpromide ; valproic acid ; pharmacokinetics ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of valpromide, a primary amide of valproic acid, was investigated in 6 healthy, adult male volunteers, each of whom was given 900 mg as a marketed, enteric-coated tablet and a solution. Valpromide was biotransformed to valproic acid after the administration of the tablet and the solution with a bioavailability of 0.79±0.24 and 0.77±0.12, respectively, relative to a marketed tablet of valproic acid. The absorption of valpromide was not rate-limited by dissolution. As a solid, non-hygroscopic, neutral prodrug of valproic acid, valpromide may be a good alternative to valproic acid and sodium valproate.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00549603
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  • 142
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    Inter- and intra-subject variation in the first-pass elimination of highly cleared drugs during chronic dosing (1984)
    Springer
    European journal of clinical pharmacology 26 (1984), S. 47-53 
    Details
    ISSN: 1432-1041
    Keywords: verapamil ; first-pass metabolism ; pharmacokinetics ; interindividual variation ; intraindividual variation ; chronic administration ; deuterated verapamil
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of verapamil in five healthy volunteers were investigated on 4 occasions during chronic administration of deuterated verapamil. There was no statistically significant difference in oral clearance, terminal half-life, bioavailability, morning trough level and peak concentration or in the time of their occurrence on the four occasions. The plasma clearance, however, exhibited considerable inter- and intra-individual variation, ranging between 26.3% and 85.4% and 12.0% and 48.0%, respectively. Comparison of these pharmacokinetic parameters with data from previous single dose studies in the same subjects revealed a significant (p〈0.05) decrease in the clearance and an increase in the apparent bioavailability of verapamil during chronic administration, although no difference in the half-life was found. Due to the considerable variation in the oral clearance of verapamil during chronic dosing, steady-state conditions in a strict pharmacokinetic sense may never be attained, and pharmacokinetic data obtained in single dose studies will be of limited value in predicting steady-state plasma concentrations.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00546708
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  • 143
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    Pharmacokinetic evaluation of haemoperfusion in phenobarbital poisoning (1984)
    Springer
    European journal of clinical pharmacology 26 (1984), S. 109-112 
    Details
    ISSN: 1432-1041
    Keywords: phenobarbital poisoning ; charcoal haemoperfusion ; distribution volume ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Charcoal haemoperfusion was performed for 5–12 h in three patients with maximal plasma phenobarbital concentrations of 600, 946 and 1044 µmol/l (138, 217 and 240 µg/ml). During haemoperfusion with constant blood flow phenobarbital elimination followed first order kinetics with half-lives of 11.1, 10.0 and 7.2 h, respectively. After termination of the haemoperfusion there was no rebound effect in plasma phenobarbital concentration and the elimination was first order with half-lives of 51, 82 and 48 h, respectively. Thus, the plasma phenobarbital half-life was reduced by 78–88% during haemoperfusion. In the same period 76–86% of the total body clearance of phenobarbital was due to the haemoperfusion column at a calculated volume of distribution of phenobarbital of 1.1–1.2 l/kg. This is clear evidence for recommending haemoperfusion in cases of serious poisoning with phenobarbital.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00546717
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  • 144
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    Pharmacokinetics of nadolol in healthy subjects (1984)
    Springer
    European journal of clinical pharmacology 26 (1984), S. 125-127 
    Details
    ISSN: 1432-1041
    Keywords: nadolol ; pharmacokinetics ; plasma levels ; urinary excretion ; bioavailability ; circadian rhythm
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In 7 healthy subjects (3 males and 4 females), the kinetics of nadolol was investigated after oral doses of 60 and 120 mg. The t1/2 was 14.0±1.8 h. The peak plasma level was doubled on doubling the dose (from 69±15 to 132±27 ng/ml, respectively) and the urinary excretion (13.5%) rose similarly. The half-life of elimination was longer at night than in the day, probably because of the slower nocturnal flow of urine.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00546720
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  • 145
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    Pharmacokinetics of furosemide in man after intravenous and oral administration. Application of moment analysis (1984)
    Springer
    European journal of clinical pharmacology 26 (1984), S. 197-207 
    Details
    ISSN: 1432-1041
    Keywords: furosemide ; bioavailability ; pharmacokinetics ; oral administration ; i.v. administration ; drug absorption ; moment analysis ; food effect ; dissolution effect
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Furosemide 40 mg was administered to 8 healthy subjects as an i.v. bolus dose, as 1 tablet in the fasting state, and as 1 tablet and a solution after food intake. The i.v. data gave a total body clearance of 162±10.8 ml/min and a renal clearance of 117±11.3 ml/min; the volume of distribution at steady state was 8.3±0.61. Oral administration gave a bioavailability of the tablet (fasting) of 51%. Food intake slightly reduced the bioavailability, but not to a significant extent. There was no significant difference in availability between the tablet and the solution. Moment analysis gave a mean residence time after the i.v. dose, MRTi.v., of 51±1.5 min. The mean absorption times (MAT) for all oral doses were significantly longer than the MRTi.v., indicating absorption rate-limited kinetics of furosemide. On average, food delayed the absorption by 60 min. The MAT for the tablet in the postprandial state was significantly longer than for the solution, indicating dissolution rate-limited absorption of the tablet.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00630286
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  • 146
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    Pharmacokinetics of epidural morphine in man (1984)
    Springer
    European journal of clinical pharmacology 26 (1984), S. 233-237 
    Details
    ISSN: 1432-1041
    Keywords: morphine ; anesthesiology ; epidural application ; pharmacokinetics ; plasma level ; CSF level
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Cerebrospinal fluid (CSF) and plasma morphine concentrations were determined in 5 patients after epidural administration of 6 mg morphine; plasma samples were collected frequently during the initial 6 h and 6–7 CSF samples were obtained from each patient over a 24 h period. Morphine was analysed using gas chromatography and electron capture detection. Individual morphine concentration-time curves were plotted for plasma and CSF and various pharmacokinetic variables were calculated. Plasma morphine concentrations after epidural injection were similar to those found after intramuscular administration; Cmax (66±8 mg/ml: mean±SEM) appeared within 12±3 min, and the terminal elimination half-life in plasma was 213±24 min. In CSF, morphine reached a peak (1575±359 ng/ml) after 135±40 min. The terminal elimination half-life for morphine in CSF was 239±10 min. The CSF bioavailability of morphine after epidural administration was calculated to be 1.9±0.5%. The study showed that epidural administration of morphine resulted in CSF concentrations many times higher than those in plasma, but still only 2% of the dose administered was available to the CSF compartment. Morphine was eliminated with similar speed from CSF and plasma.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00630291
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  • 147
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    Pharmacokinetic and pharmacodynamic modelling with pancuronium (1984)
    Springer
    European journal of clinical pharmacology 26 (1984), S. 243-250 
    Details
    ISSN: 1432-1041
    Keywords: pancuronium ; neuromuscular relaxants ; simultaneous modelling ; pharmacokinetics ; pharmacodynamics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics and pharmacodynamics of pancuronium were studied following intravenous infusion in eleven patients undergoing surgical anaesthesia. Measurement of the plasma concentrations (Cp) of the neuromuscular blocking agent (NMBA) and the concomitant intensities of paralysis allowed their simultaneous modelling. The pharmacokinetic parameters derived for pancuronium were in the range of previously reported values, except that the mean total systemic plasma clearance (0.79±0.28 ml·min−1·kg−1) was reduced and the mean terminal phase half-life (169 min) was longer in these patients. Plasma concentration and % paralysis data were successfully fitted to a previously proposed pharmacodynamic model. This model assumes a separate effect compartment which exchanges drug directly with the central kinetic compartment (integrated effect model). The ‘steady-state’ Cp necessary to produce 50% paralysis (ECpss(50)) was estimated to be 0.21±0.08 µg·ml−1 (mechanical response) and 0.18±0.05 µg·ml−1 (EMG response). An analysis using the Hill equation of the Cp-response relationship, during and after the constantrate infusion of pancuronium bromide, resulted in effective plasma concentrations for 50% paralysis (ECp50) of 0.35±0.06 µg·ml−1 and 0.20±0.09 µg·ml−1, respectively, for mechanical twitch response. The corresponding values for EMG response were 0.32±0.06 µg·ml−1 and 0.17±0.06 µg·ml−1. Using this latter approach, the ECp50 estimated during onset of paralysis was significantly higher than that estimated during offset of paralysis (p〈0.05); no such difference was apparent between this latter parameter and the ECpss(50) of the integrated effect model (p〉0.05). No significant differences were observed between any of the pharmacodynamic parameter estimates generated from the data obtained from the two methods of assessment of neuromuscular function (mechanical vs. EMG response) (p〉0.05).
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00630293
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  • 148
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    Effect of aluminium phosphate on the bioavailability of cimetidine and prednisolone (1984)
    Springer
    European journal of clinical pharmacology 26 (1984), S. 271-273 
    Details
    ISSN: 1432-1041
    Keywords: cimetidine ; prednisolone ; aluminium phosphate ; antacids ; bioavailability ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Ten fasting subjects received 200 mg cimetidine orally either with water or 11 g aluminium phosphate mixture in a randomized, single dose, two-way cross-over study. Blood samples were taken for 12 h and urine was collected for 24 h. Cimetidine in plasma and urine was analysed by HPLC. There were no significant differences between the treatments with respect to peak plasma concentration, time to peak plasma concentration, area under the plasma concentration-time curve, and urinary excretion. In 12 healthy subjects the absorption of prednisolone was investigated when given alone and together with 11 g aluminium phosphate. Blood samples were taken over 16 h and prednisolone in plasma was analysed by HPLC. There were no significant differences in the values of area under curve (AUC), Cmax and tmax. The results indicate that aluminium phosphate does not reduce the bioavailability of cimetidine and prednisolone.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00630299
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  • 149
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    Electronic Resource
    Pharmacokinetics of cimetidine in advanced cirrhosis (1984)
    Springer
    European journal of clinical pharmacology 26 (1984), S. 347-355 
    Details
    ISSN: 1432-1041
    Keywords: cimetidine ; cirrhosis ; pharmacokinetics ; bioavailability ; clearance reduction
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effect of impaired liver function on the pharmacokinetics of cimetidine was studied in 8 patients with advanced cirrhosis given single doses of 100 mg i.v. and 400 mg p.o. on separate days. Compared to a control group of 10 healthy volunteers, the total renal and nonrenal clearance was significantly reduced in the cirrhotic patients; (total plasma clearance mean ± SD) 356±181 vs 789±262 ml/min (p〈0.01); renal clearance (Clr) 296±100 vs 588±181 ml/min (p〈0.01) and nonrenal clearance (Clnr) 97±111 vs 205±89 ml/min (p〈0.05). Compared to published results for age-matched ulcer patients, both total and nonrenal clearance were lower whereas renal clearance was within the reported normal range. A significant reduction in volume of distribution (Vdβ) was found, from 2.1±0.1 l/kg in controls to 1.0±0.4l/kg, and in the patient group there was a significant correlation between Vdβ and total plasma clearance (r=0.72, p〈0.05). Volume of distribution in steady state (Vdss) did not differ from published results in age-matched controls. No significant change in half-life was found. Bioavailability, estimated by AUC-measurement, showed considerable patient variability (21–143%), with a mean of 70±39%. This was lower than in the controls. In contrast, measurement of urinary excretion showed higher bioavailability in the patients (66±23 vs 51±8%). No correlation was found between any of the kinetic parameters and the clinical and laboratory data. It is suggested that patients with advanced cirrhosis should be closely observed when given cimetidine, and a reduction in dose should be concidered if side effects are to be avoided.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00548766
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  • 150
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    Steady state pharmacokinetics of trimethoprim 300 mg once daily in healthy volunteers assessed by two independent methods (1984)
    Springer
    European journal of clinical pharmacology 26 (1984), S. 393-397 
    Details
    ISSN: 1432-1041
    Keywords: trimethoprim ; concentration ; urinary excretion ; healthy volunteers ; steady state ; pharmacokinetics ; serum creatinine
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The steady state pharmacokinetics of trimethoprim was determined after 300 mg orally once daily to 6 healty volunteers for 9 days. The microbiological assay of plasma level was unreliable at trimethoprim concentrations 〉4 µg/ml, so results from an HPLC-assay are given. Steady state was present after 3 days. The plasma concentration peaked 1 to 4 h (mean 2.0 h) after the dose at a mean of 6.0 µg/ml (range 3.1–9.5 µg/ml); the minimum value was 1.5 µg/ml (range 0.6–2.9 µg/ml). The mean AUCss was 77 µg/ml · h and the mean plasma clearancess was 67 and 74 ml/min on Days 8 and 9. Renal clearance was about 60% of the plasma clearance. The average plasma half life was 10.6 h (range 8.7–15.3 h). Thus, there was considerable interindividual variation in all pharmacokinetic parameters. 72 h after the last dose trimethoprim was detectable in plasma in only 1 of the 6 subjects. The minimum urinary concentration of trimethoprim during treatment was always well above (range 22 to 220 µg/ml) the MIC values for most urinary tract pathogens. Therefore, a daily dose of 300 mg trimethoprim results in a therapeutic concentration in urine at steady state that lasts throughout the dosing interval and in most subjects probably lasts also for a further 24 h. Trimethoprim administration raised mean serum creatinine from 67 to 97 µmol/l, probably due to competitive inhibition of the tubular secretion of creatinine.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00548773
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  • 151
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    Comparison of the short-term effects of the loop diuretic piretanide and furosemide in patients with renal insufficiency (1984)
    Springer
    European journal of clinical pharmacology 26 (1984), S. 413-418 
    Details
    ISSN: 1432-1041
    Keywords: piretanide ; furosemide ; renal insufficiency ; loop diuretic ; natriuresis ; pharmacokinetics ; diuretic effect ; kaliuresis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The natriuretic effect of the new loop diuretic piretanide was investigated in patients with severe renal insufficiency and was compared with that of furosemide. In the first study 4 hospitalized patients (serum creatinine 407 to 1220 µmol/l) were examined after administration of piretanide (12, 24, 48 and 96 mg to two patients, and 24, 48, 96 and 192 mg to 2 other subjects, given every third day). In the second study 6 hospitalized patients (serum creatinine 194 to 698 µmol/l) were studied after receiving orally 2 different doses of piretanide and 2 different doses of furosemide orally, given every fourth day. The mean natriuretic effect of 48 mg and 96 mg piretanide was 250 and 340% of the control value for the entire group, and 311 to 480% in the subgroup of patients with serum creatinine below 530 µmol/l. For a given dose the natriuresis was inversely correlated with renal function, and at a given serum creatinine level the natriuretic response was dose-dependent. The drug had less effect on water and potassium diuresis than on natriuresis. No significant difference in natriuretic effect was found on comparison with furosemide given in the ratio furosemide: piretanide 3.33:1. The pharmacokinetic data showed a direct correlation between the dose and the mean plasma concentration and also between urinary recovery of the drug and the measured natriuretic response.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00542133
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  • 152
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    Individualizing theophylline dosage: Evaluation of a single-point maintenance dose prediction method (1984)
    Springer
    European journal of clinical pharmacology 26 (1984), S. 491-498 
    Details
    ISSN: 1432-1041
    Keywords: theophylline ; computer simulation ; pharmacokinetics ; single-point dose prediction ; nomogram
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary A dosage prediction method to estimate theophylline clearance and dose requirement was evaluated in 22 outpatients with partly reversible obstructive airways disease. The steady state theophylline dose required to achieve a target concentration (Css) was predicted using a single serum theophylline determination 8 h after a single oral test dose. In 17 nonsmoking patients a mean absolute deviation of 8.2% (range 0.0–21.7%) between predicted and observed Css was found, and in 5 smoking patients the mean deviation was 34.0% (range 2.2–53.8%). In 17 healthy smokers the single-point method was found to predict theophylline clearance at a sampling time of 8 h with a prediction error of 11.3 (range 0.8–25.3%) compared to the clearance determination using the area under the curve. In addition, a numerical simulation program to assess the influence of absorption, elimination and sampling time on predictive accuracy showed that the method could be successfully applied to a patient population with elimination rate constants between 0.07 1/h and 0.25 1/h, allowing a mean prediction error of 15%.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00542147
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  • 153
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    Comparison of radioreceptor assay and radioimmunoassay for atropine: Pharmacokinetic application (1984)
    Springer
    European journal of clinical pharmacology 26 (1984), S. 613-617 
    Details
    ISSN: 1432-1041
    Keywords: atropine ; radioreceptor assay ; radioimmunoassay ; serum levels ; pharmacokinetics ; assay comparison
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary A membrane suspension prepared from rat brain was able to bind the potent muscarinic antagonist quinuclidinyl benzilate (QNB). The KD for binding was 0.48 nM and Bmax was 1.42 pmol/mg protein. Atropine competitively inhibited the binding of tritiated QNB to muscarinic receptors. This new radioreceptor assay (RRA) for atropine has been compared with a radioimmunoassay (RIA) for atropine. The RRA measures only the active component of atropine, 1-hyscyamine and in this respect it differs from the RIA. As little atropine as 1.25 ng/ml (4.33 nmol/l) in a 25 µl serum sample could be reliably assayed by the RRA. Using both assay techniques the pharmacokinetics of atropine was studied after a single 0.02 mg/kg i.v. dose given to 8 anaesthetized patients. The half-life calculated by the RRA was 3.7±2.3 h (m ± SD) and by the RIA 4.3±1.7 h. Both the volume of distribution and the total clearance were higher according to the RRA than the RIA: 3.9±1.5 vs 1.7±0.71/kg and 15.4±10.3 vs 5.9±3.6 ml/min/kg, respectively. The AUC measured by the RRA and RIA was 29.8±18.9 and 103.9±110.7 µg·h/l, respectively. The differences in the pharmacokinetics according to the 2 methods are presumably due to preferential tissue uptake of the l-form.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00543495
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  • 154
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    Oral pharmacokinetics of omeprazole (1984)
    Springer
    European journal of clinical pharmacology 26 (1984), S. 641-643 
    Details
    ISSN: 1432-1041
    Keywords: omeprazole ; gastric acid secretion ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of omeprazole were studied in a group of healthy male subjects after single and repeated oral doses of 30 and 60 mg. Absorption of omeprazole from its enteric-coated formulation was unpredictable. There was a highly significant increase in the area under the plasma concentration time curve (AUC) after repeated dosing. Omeprazole increases its own relative availability following repeated dosing. This may be due to inhibition of gastric acid secretion by omeprazole which is an acid-labile compound.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00543502
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  • 155
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    Bioavailability and pharmacokinetics of phenytoin during pregnancy (1984)
    Springer
    European journal of clinical pharmacology 27 (1984), S. 105-110 
    Details
    ISSN: 1432-1041
    Keywords: phenytoin ; epileptic women ; pharmacokinetics ; bioavailability ; pregnancy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Five epileptic women needing to commence phenytoin therapy during pregnancy received a single intravenous and a single oral dose of phenytoin several days apart before starting regular intake of the drug. Plasma phenytoin concentration — time data were analysed by three different pharmacokinetic techniques. However assessed, the mean oral bioavailability of the drug proved to be about 90% of the intravenous bioavailability. This finding makes it unlikely that impaired bioavailability accounts for the increase in oral phenytoin dosage necessary in pregnancy to maintain plasma phenytoin concentrations at pre-pregnancy values. Phenytoin clearance in the pregnant subjects was approximately double the published values for phenytoin clearance in nonpregnant persons. This suggests that increased (metabolic) clearance accounts for the increased phenytoin dosage requirement of pregnancy.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00553163
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  • 156
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    Effect of food on pharmacokinetics of chlorambucil and its main metabolite, phenylacetic acid mustard (1984)
    Springer
    European journal of clinical pharmacology 27 (1984), S. 111-114 
    Details
    ISSN: 1432-1041
    Keywords: chlorambucil ; chronic lymphocytic leukaemia ; phenylacetic acid mustard ; food intake ; pharmacokinetics ; bioavailability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The influence of food intake on the pharmacokinetics of chlorambucil (C) and its cytotoxic metabolite, phenylacetic acid mustard (PAM), has been studied in man after oral doses of chlorambucil. The administration of chlorambucil with food resulted in slower absorption than when fasting. However, the area under the plasma concentration-time curve (AUC) was unaffected. The mean ratio AUCPAM/AUCC was 2.8 (range 1.4–7.1) under fasting and 3.3 (range 1.3–7.4) under nonfasting conditions. The metabolite very probably plays an important role in the cytotoxic effects observed after administration of C, since calculations show that a major fraction of the metabolite is eliminated by alkylation reactions.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02395216
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  • 157
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    Pharmacokinetics of S-adenosyl-L-methionine in healthy volunteers (1984)
    Springer
    European journal of clinical pharmacology 27 (1984), S. 119-121 
    Details
    ISSN: 1432-1041
    Keywords: S-adenosyl-L-methionine ; pharmacokinetics ; protein binding ; dose-dependent kinetics ; healthy volunteers ; urinary excretion
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary S-Adenosyl-L-methionine (AdoMet) kinetics was studied in 6 male subjects given 100 and 500 mg i. v. Drug concentrations in plasma and urine were assayed using a radioenzymatic method. Pharmacokinetic parameters were estimated according to an open two-compartment model. The apparent volumes of distribution after the 100 and 500 mg doses were 407±27 and 443±36 ml/kg (mean±SEM), terminal half-lives 81±8 and 101±7 min and body clearances 3.7±0.5 and 3.1±0.2 ml/min per kg. Urinary excretion was 34±3 and 40±2% of the administered dose. The results demonstrate that drug disposition occurs more via metabolism than via renal excretion, and it is not dependent on the administered dose. Binding of AdoMet to serum proteins is negligible.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02395218
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  • 158
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    Papaverine disposition in cardiac surgery patients and the effect of cardiopulmonary bypass (1984)
    Springer
    European journal of clinical pharmacology 27 (1984), S. 127-130 
    Details
    ISSN: 1432-1041
    Keywords: papaverine ; cardiopulmonary bypass ; pharmacokinetics ; cardiac surgery patients
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Cardiac surgery involving cardiopulmonary bypass (CPB) causes substantial physiologic changes which may potentially alter the pharmacokinetic properties of drugs used during and after the procedure. Studies with fentanyl have implied a relationship between prolonged elimination half-lives following CPB and decreased liver perfusion during and after the procedure. To further test this hypothesis, the effects of CPB on the pharmacokinetics of papaverine, a coronary vasodilator currently being added to the cardioplegic solution to prevent vasospasm, were studied. The drug was given to two groups of patients, one (n=6) undergoing surgery with and one (n=5) without CPB, the latter serving as controls. Plasma papaverine concentrations declined biexponentially in the control patients with a mean elimination half-life of 1.30±0.25 h, total plasma clearance of 13.8±3.75 ml/min/kg, volume of distribution of 1.52±0.45 l/kg and volume of distribution, steady-state, of 0.992±0.530 l/kg. For the CPB group, only half-life was estimated, and averaged 2.77±0.28 h, significantly greater (p〈0.01) than that in the controls. These results further confirm the increased half-lives seen with other hepatically cleared drugs following CPB and have implications in the clinical management of patients given drugs eliminated in this manner.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00544033
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  • 159
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    Pharmacokinetics of meptazinol after single and multiple oral administration to elderly patients (1984)
    Springer
    European journal of clinical pharmacology 27 (1984), S. 223-226 
    Details
    ISSN: 1432-1041
    Keywords: meptazinol ; pharmacokinetics ; multiple dosing ; elderly patients
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Oral administration of meptazinol (200 mg Meptid®) to male and female geriatric patients (〉70 years) resulted in rapid absorption, with peak drug concentrations at 0.5 to 3 h after dosage. Subsequent elimination also proceeded rapidly with a half-life of 3.39 h (±0.26 SEM) after a single dose and 4.97 h (±0.80 SEM) after 13 consecutive 6-h doses. These values were not statistically different. There was no accumulation of meptazinol above that expected from the single-dose kinetics. Plasma protein binding of meptazinol was 33.8% (±0.74 SEM). No sex difference was apparent in any of the pharmacokinetic parameters determined. Comparison of these results with those obtained in an earlier study in young volunteers showed that although the half-life of meptazinol was somewhat longer than the value of 2 h seen in the young, peak plasma concentrations after single and multiple dosing were similar for both age groups, implying that clearance remained largely unaltered. It was concluded that there was no pharmacokinetic basis for recommending a reduction in dosage when treating elderly patients with oral meptazinol.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00544049
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  • 160
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    Identification of a prazosin metabolite and some preliminary data on its kinetics in hypertensive patients (1984)
    Springer
    European journal of clinical pharmacology 27 (1984), S. 275-280 
    Details
    ISSN: 1432-1041
    Keywords: prazosin ; hypertensive patients ; prazosin metabolite ; HPLC assay ; pharmacokinetics ; hypotensive effect
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary A metabolite of prazosin was detected in serum from hypertensive patients treated with prazosin. Its structure as 2-(1-piperazinyl)-4-amino-6,7-dimethoxyquinazoline was established by UV, IR, and mass-spectrometry. An assay method for simultaneous determination of prazosin and its metabolite in serum, urine and saliva is described. Preliminary data about the kinetics of prazosin and the metabolite after a single oral dose of prazosin 1 mg, and after multiple doses of 1 to 5 mg t.i.d. for 6–82 days in 7 patients with hypertension, are presented. After the single dose the metabolite level was much lower than that of intact drug, even though the former was eliminated much more slowly than the latter. The slow elimination of the metabolite led to its eventual accumulation in serum during multiple administration. The mean accumulation ratio of the metabolite was estimated to be at least 5.5 (from 3.0 to 7.9). Prazosin itself had a low accumulation ratio, so the mean steady-state level of the intact drug on multiple administration was several times lower than that of metabolite. As this metabolite has some hypotensive effect in animals, it may account for part of the therapeutic activity of parzosin in patients. The mean steady-state concentration of intact prazosin during the course of treatment were found to be significantly lower than that predicted from a single dose study.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00542159
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  • 161
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    Effect of cimetidine and ranitidine on carbamazepine and sodium valproate pharmacokinetics (1984)
    Springer
    European journal of clinical pharmacology 27 (1984), S. 341-343 
    Details
    ISSN: 1432-1041
    Keywords: cimetidine ; ranitidine ; carbamazepine ; sodium valproate ; pharmacokinetics ; drug metabolism ; inhibition
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of a single oral dose (400 mg) of carbamazepine and sodium valproate were compared in peptic ulcer patients before and after four weeks of a therapeutic course of either cimetidine (1 g/day, n=6 subjects) or ranitidine (300 mg/day, n=6 subjects). There was a small (up to 20%) but statistically significant decrease in oral clearance of carbamazepine after cimetidine treatment. A similar fall in sodium valproate clearance in five cimetidine-treated patients was accompanied by a significantly prolonged elimination half-life. No such trends were demonstrated during ranitidine treatment. Since both anticonvulsants are partly metabolized by hepatic mixed function oxidases, an inhibition by cimetidine at this level may be responsible for the observed impairment of clearance. Thus a potentially important clinical interaction may occur in patients taking anticonvulsants and cimetidine concurrently.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00542172
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  • 162
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    Pharmacokinetics and pharmacodynamics of a novel orally active angiotensin converting enzyme inhibitor (HOE 498) in healthy subjects (1984)
    Springer
    European journal of clinical pharmacology 27 (1984), S. 577-581 
    Details
    ISSN: 1432-1041
    Keywords: HOE 498 ; ACE inhibitor ; pharmacokinetics ; pharmacodynamics ; urinary excretion
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics and pharmacodynamics of the angiotensin converting enzyme inhibitor HOE 498 were investigated in 10 healthy normotensive male subjects. Serum levels of the active metabolite M 1 (dicarboxylic acid) of HOE 498 were measured by HPLC up to 14 days after a single oral dose of 10 m g HOE 498. Peak serum concentration of M 1 between 5–50 ng/ml was observed 1.5–3.0 h after administration. The serum concentration-time curve of M 1 was polyphasic and exhibited a prolonged terminal phase with a half-life of approximately 110 h. Despite the long terminal half-life M 1 could not be detected in urine later than 72 h after administration. The activity of the angiotensin converting enzyme in plasma was completely suppressed for up to 12 h, and 72 h after dosing 50% inhibition of the enzyme was still observed.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00556895
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  • 163
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    Pharmacokinetics and pharmacodynamics of transdermally administered clonidine (1984)
    Springer
    European journal of clinical pharmacology 26 (1984), S. 79-85 
    Details
    ISSN: 1432-1041
    Keywords: clonidine ; transdermal application ; pharmacodynamic effect ; pharmacokinetics ; side effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Clonidine was applied to the skin of healthy volunteers once weekly by means of a Transdermal Therapeutic System (TTS). The plasma concentration and renal excretion of clonidine, and its effects on mean arterial blood pressure (MAP) and heart rate (HR) were recorded for 7 days, followed by a three-day observation period when a second TTS was applied. Subjective side effects were semiquantitatively recorded. Four differents TTS formulations were tested; of which TTS-RP 600679 was the most effective. Following application of this formulation, the plasma level of the drug built-up up during the first 2 days and then remained stable for 120 h at therapeutic concentrations between 0.5 and 0.7 ng/ml; MAP was consistently reduced. During the steady state period the daily urinary clonidine excretion was in the same range as during chronic administration of Catapres tablets 0.15 mg every 12 h, or Catapres Perlongets 0.25 mg every 24 h. Transdermal clonidine applications renewed weekly provide the following therapeutic advantages: 1. patients are protected continuously throughout the entire steady state period; 2. daily fluctuations in plasma clonidine concentration are minimized, which may result in a marked reduction in side effects; and, 3. drug compliance should be improved.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00546713
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  • 164
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    Effect of a reversible and selective MAO-A inhibitor (cimoxatone) on diurnal variation in plasma prolactin level in man (1984)
    Springer
    European journal of clinical pharmacology 26 (1984), S. 71-77 
    Details
    ISSN: 1432-1041
    Keywords: cimotaxone ; MAO inhibitor ; plasma prolactin ; circadian rhythm ; healthy volunteers ; hypothalamic MAO ; prolactin secretion ; metabolism ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Prolactin (PRL) secretion is stimulated by serotonin (5-HT) and inhibited by dopamine (DA). 5-HT is generally recognized as a substrate for type A monoamine oxidase (MAO), whereas DA is considered as a substrate for either A or B, or both forms of MAO, depending on the species and tissues used. The effect of cimoxatone, a reversible, selective MAO-A inhibitor, on diurnal variation in plasma PRL level was investigated in healthy adults after a single 40 mg oral dose, as an indirect approach to investigating whether DA is preferentially a substrate for Type A or B MAO in man. The circadian rhythm in PRL, stress conditions and diet were taken into account in the present study, which was placebo-controlled. There was a slight but significant reduction in circulating PRL in the six subjects, which persisted for at least 9 h after cimoxatone. However, the duration of the decrease in plasma PRL was shorter than the inhibition of MAO-A. The results are not inconsistent with the presence of both forms of MAO in the human hypothalamus and with DA as a substrate for both forms in this region, if it is assumed that the hypothalamic concentrations of the drug during the period 0–9 hours was sufficiently high to inhibit DA deamination by both forms of MAO.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00546712
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  • 165
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    Dose-dependent pharmacokinetics of aprindine in healthy volunteers (1984)
    Springer
    European journal of clinical pharmacology 26 (1984), S. 129-131 
    Details
    ISSN: 1432-1041
    Keywords: aprindine ; antiarrhythmic agent ; healthy volunteers ; plasma level ; oral administration ; pharmacokinetics ; urinary excretion
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The disposition of aprindine following a single oral dose can best be described by a two-compartment open model. The mean plasma half-life (t1/2β) increased from 8.0±2.1 h (SD) after a 25 mg dose to 9.4±2.9 h after 50 mg and to 15.8±2.6 h after 100 mg, with a decrease in total plasma clearance (Cl/F) and volume of distribution at steady state (Vdss/F) and during β-phase (Vdβ/F). The area under plasma concentration-time curve (AUC), maximum plasma concentration (Cmax) and the amount of unchanged aprindine excreted in the urine increased in a non-linear fashion with the increase in dose. The t1/2β after multiple oral doses showed a 3-fold increase over the single dose value. These results indicate that aprindine shows dose-dependent non-linear kinetics.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00546721
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  • 166
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    Pharmacokinetic and pharmacodynamic study of the combination of furosemide retard and triamterene (1984)
    Springer
    European journal of clinical pharmacology 26 (1984), S. 191-195 
    Details
    ISSN: 1432-1041
    Keywords: furosemide ; triamterene ; drug combination ; pharmacodynamics ; pharmacokinetics ; furosemide retard ; triamterene metabolite ; urine potassium
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacodynamics and pharmacokinetics of the combination of furosemide retard (30 mg)/triamterene (50 mg) were compared with furosemide (30 mg) in 18 healthy male volunteers aged 39.3±6.3 years. After the administration of furosemide the onset of its effect was very rapid, reaching a maximum between 1.5 to 3 h, and followed by rebound after 9 to 10.5 h. In contrast the combination furosemide retard/triamterene showed a protracted course with a duration of effect up to 12 h. The general effect over 12 h of the two preparations was equivalent with respect to the excretion of urine, sodium, chloride and calcium, but the combination caused significantly less excretion of potassium (p≤0.05) than furosemide. After a lag-phase of 33.9±5.4 min the maximum plasma concentration of furosemide was reached after 3.47±0.66 h, and the elimination half-life was approximately 2 h. After a lag-phase of 33.0±17.8 min the maximum plasma concentration of the main metabolite of triamterene, the OH-TA sulphuric acid ester, was reached after 1.7±0.59 h, and its elimination half-life amounted to 1.25±0.37 h. Because of the sustained release of furosemide from the retard-formulation, its principal pharmacokinetic parameters were better adapted to those of triamterene. The consequences were not only a protracted effect but also an improved electrolyte profile, especially with regard to reduced loss of potassium. In the case of renal insufficiency, however, the potassium level in serum might be increased to an undesirable extent.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00630285
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  • 167
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    Electronic Resource
    Bioavailability of cyclophosphamide from oral formulations (1984)
    Springer
    European journal of clinical pharmacology 26 (1984), S. 269-270 
    Details
    ISSN: 1432-1041
    Keywords: cyclophosphamide ; cytostatic drug ; cancer therapy ; female breast cancer ; bioavailability ; rapid release formulations ; gastric juice resistant formulation ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Cyclophosphamide (CP) is an alkylating cytostatic compound, which is activated to its cytotoxic form in the liver [1]. Since the therapeutic range of CP in the treatment of human tumours, is small like other cytostatics, a constant high bioavailability is essential for its oral administration. Although CP has become one of the most widely used cytostatics [2], there do not appear to have been any bioavailability investigations providing the necessary information. The development of a very sensitive gas chromatographic analytical method has now permited investigation of the pharmacokinetics of oral CP in conventional clinical doses [3, 4, 5, 6].
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00630298
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  • 168
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    Pharmacokinetics and hypotensive effect in healthy volunteers of pinacidil, a new potent vasodilator (1984)
    Springer
    European journal of clinical pharmacology 26 (1984), S. 603-608 
    Details
    ISSN: 1432-1041
    Keywords: pinacidil ; hypertension ; pinacidil pyridine-N-oxide ; urinary excretion ; protein binding ; pharmacokinetics ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Preliminary investigation in 3 healthy volunteers suggested that intravenous pinacidil in a dose of 0.2 mg/kg had a potent but well-tolerated hypotensive action in the supine position. Facial flushing, uncomfortable chest sensation and distressing postural hypotension occurred at serum concentrations above 300 ng/ml. Pinacidil, 0.2 mg/kg, was given intravenously over 4 min to 15 healthy volunteers in the supine position. Maximum fall in mean arterial pressure (MAP) was 15.7±6.0 mmHg. Maximum rise in heart rate was 23.8±6.6 beats/min. Pinacidil serum distribution half-life ( $${\text{T}}_{{\raise0.7ex\hbox{${\text{1}}$} \!\mathord{\left/ {\vphantom {{\text{1}} {{\text{2}}\alpha }}}\right.\kern-\nulldelimiterspace}\!\lower0.7ex\hbox{${{\text{2}}\alpha }$}}}$$ ) was 13.4±8.5 min and elimination half-life ( $${\text{T}}_{{\raise0.7ex\hbox{${\text{1}}$} \!\mathord{\left/ {\vphantom {{\text{1}} {{\text{2}}\beta }}}\right.\kern-\nulldelimiterspace}\!\lower0.7ex\hbox{${{\text{2}}\beta }$}}}$$ ) was 2.13±0.49 h. The apparent volume of distribution (Vdβ) was 90.3±13.21 and total body clearance was 31.1±9.61/h. Pinacidil was approximately 40% bound to plasma protein over the concentration range 40–400 ng/ml. Urinary excretion of unchanged pinacidil accounted for 5.7 ± 1.3% of the administered dose over 24 hours and urinary excretion of the major metabolite, pinacidil pyridine-N-oxide, was 31.6±9.2% of the administered dose. It was concluded that intravenous pinacidil is a potent vasodilator hypotensive compound, with a duration of action between 1.5 and 2 h.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00543493
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  • 169
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    Pharmacokinetics and bioavailability of digitoxin by a specific assay (1984)
    Springer
    European journal of clinical pharmacology 27 (1984), S. 85-89 
    Details
    ISSN: 1432-1041
    Keywords: digitoxin ; radioimmunoassay ; pharmacokinetics ; bioavailability ; digitoxin metabolites
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics and bioavailability of digitoxin were examined in six normal human subjects using an assay that separates digitoxin from its metabolites. After intravenous administration, the mean systemic clearance was 2.44 ml/min; the volume of distribution was 0.47 l/kg; and the elimination half-life was 6.5 days. After oral administration, the elimination half-life was 5.8 days. The bioavailability was 81.5% using the specific assay. Using a non-specific, direct serum digitoxin radioimmunoassay the bioavailability was 98.0%. Assay of aqueous fractions from extracted serum samples indicated higher levels of water-soluble metabolites following oral compared to intravenous digitoxin administration. These findings suggest that previously reported values for digitoxin bioavailability using non-specific methods may be falsely elevated due to the presence of digitoxin metabolites in serum.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02395212
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  • 170
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    Electronic Resource
    Pharmacokinetics and bioavailability of digitoxin by a specific assay (1984)
    Springer
    European journal of clinical pharmacology 27 (1984), S. 85-89 
    Details
    ISSN: 1432-1041
    Keywords: digitoxin ; radioimmunoassay ; pharmacokinetics ; bioavailability ; digitoxin metabolites
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics and bioavailability of digitoxin were examined in six normal human subjects using an assay that separates digitoxin from its metabolites. After intravenous administration, the mean systemic clearance was 2.44 ml/min; the volume of distribution was 0.47 l/kg; and the elimination half-life was 6.5 days. After oral administration, the elimination half-life was 5.8 days. The bioavailability was 81.5% using the specific assay. Using a non-specific, direct serum digitoxin radioimmunoassay the bioavailability was 98.0%. Assay of aqueous fractions from extracted serum samples indicated higher levels of water-soluble metabolites following oral compared to intravenous digitoxin administration. These findings suggest that previously reported values for digitoxin bioavailability using non-specific methods may be falsely elevated due to the presence of digitoxin metabolites in serum.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00553160
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  • 171
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    Pharmacokinetics of S-adenosyl-L-methionine in healthy volunteers (1984)
    Springer
    European journal of clinical pharmacology 27 (1984), S. 119-121 
    Details
    ISSN: 1432-1041
    Keywords: S-adenosyl-L-methionine ; pharmacokinetics ; protein binding ; dose-dependent kinetics ; healthy volunteers ; urinary excretion
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary S-Adenosyl-L-methionine (AdoMet) kinetics was studied in 6 male subjects given 100 and 500 mg i. v. Drug concentrations in plasma and urine were assayed using a radioenzymatic method. Pharmacokinetic parameters were estimated according to an open two-compartment model. The apparent volumes of distribution after the 100 and 500 mg doses were 407±27 and 443±36 ml/kg (mean±SEM), terminal half-lives 81±8 and 101±7 min and body clearances 3.7±0.5 and 3.1±0.2 ml/min per kg. Urinary excretion was 34±3 and 40±2% of the administered dose. The results demonstrate that drug disposition occurs more via metabolism than via renal excretion, and it is not dependent on the administered dose. Binding of AdoMet to serum proteins is negligible.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00553166
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  • 172
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    Pharmacokinetics of the selective benzodiazepine antagonist Ro 15-1788 in man (1984)
    Springer
    European journal of clinical pharmacology 27 (1984), S. 115-117 
    Details
    ISSN: 1432-1041
    Keywords: benzodiazepine antagonist ; Ro 15-1788 ; healthy volunteers ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of the selective benzodiazepine antagonist Ro 15-1788 has been studied in 6 healthy male volunteers following a single intravenous dose of 2.5 mg. The drug was only slightly bound to plasma proteins (40±8%, mean±SD). A negligible amount (〈0.2% of the dose) of unchanged drug was recovered in urine. Hepatic elimination was rapid, as shown by a short t1/2 of 0.9±0.2 h, and high total plasma and blood clearances of 691±216 ml/min and 716±199 ml/min, respectively. The fast decline of plasma levels from about 60 to 2 ng/ml accounts for the short-lasting reversal of benzodiazepine-induced sedation by Ro 15-1788.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02395217
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  • 173
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    Pharmacokinetics and pharmacodynamics of the ergot derivative, transdihydrolisuride, in man (1984)
    Springer
    European journal of clinical pharmacology 27 (1984), S. 335-339 
    Details
    ISSN: 1432-1041
    Keywords: transdihydrolisuride ; dopamine agonist ; pharmacokinetics ; pharmacodynamics ; prolactin levels ; side-effects ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Plasma levels and urinary excretion of the dopamine agonist, transdihydrolisuride (TDHL), were measured by radioimmunoassay in healthy male volunteers given TDHL 50 µg i.v. and oral doses of 200, 400 and 800 µg. Plasma prolactin was also measured by radioimmunoassay. Following i.v. injection, the concentration of TDHL declined with a half-life of 37±19 min. The total clearance was 38±27 ml/min/kg and the apparent volume of distribution was 1.3±0.4 l/kg. The bioavailability of oral TDHL was proportional to the dose; after 200, 400 and 800 µg the bioavailability was 20±25%, 31±24% and 48±26%. TDHL was almost totally metabolized and less than 0.5% of the dose was excreted unchanged in urine in 24 h. Plasma prolactin levels were depressed by 66±15%, 75±11% and 80±7% after TDHL 200 µg, 400 µg and 800 µg. The effect lasted for more than 12 h after the lowest dose and for more than 24 h after 400 and 800 µg. Side effects, mainly nausea and headache, only occurred at the two highest dose levels.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00542171
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  • 174
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    Intravenous and oral administration of molsidomine, a pharmacodynamic and pharmacokinetic study (1984)
    Springer
    European journal of clinical pharmacology 27 (1984), S. 203-208 
    Details
    ISSN: 1432-1041
    Keywords: molsidomine ; vasodilators ; pharmacokinetics ; pharmacodynamics ; dose-response relationship ; haemodynamics ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In 12 healthy male volunteers, molsidomine 1, 2 and 4 mg i.v. increased resting heart rate and decreased systolic blood pressure, the latter still being affected after 8 hours. After single oral doses of 1 and 2 mg, systolic pressure tended to be reduced for 90 minutes and exercise heart rate tended to be increased. After oral treatment with 2 mg molsidomine three times daily for 1 week, the pharmacokinetic parameters and the effects on heart rate and blood pressure after the final dose were not different from those after the first dose. The terminal half-life was independent of dose and route of administration. Clearance and distribution volume were not dose-dependent. The bioavailability of a 2 mg oral dose of molsidomine was 44%. Inter-individual variation in heart rate, blood pressure and pharmacokinetics was observed.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00544046
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  • 175
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    Pharmacokinetics of tolfenamic acid: Disposition in bile, blood and urine after intravenous administration to man (1984)
    Springer
    European journal of clinical pharmacology 27 (1984), S. 349-354 
    Details
    ISSN: 1432-1041
    Keywords: tolfenamic acid ; anti-inflammatory agents ; biliary excretion ; pharmacokinetics ; intravenous administration ; bile duct cannulation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary To study its pharmacokinetics and especially its biliary excretion, 14C-tolfenamic acid 9.84 µCi/100 mg was infused i.v. in 8 patients with a T-tube inserted in the common bile duct at choledocholithotomy 7–10 days prior to the study. Bile was collected in fractions by continuous suction over a 24 h period. Blood samples were taken and urine collected up to 48 h after the dose. Tolfenamic acid and its metabolites were separated by TLC and were quantitated by liquid scintillation counting. The pharmacokinetics of tolfenamic acid could be described by a two compartment open model with V1 of 3.67±0.68 l and Vss of 8.0±1.0 l. The total plasma clearance of tolfenamic acid averaged 106±8 ml/min and t1/2β was 1.38±0.32 h. A three compartment open model was required to describe the kinetics of total 14C. The plasma clearance of total 14C was 15.4±3.9 ml/min and its terminal half life averaged 19.0±4.1 h. The long half-life was caused by the slow elimination of tolfenamic acid metabolites. Four metabolites were measured in plasma and bile. The principal metabolites in bile were glucuronide/sulphate conjugates of hydroxylated derivatives of tolfenamic acid. The recovery of tolfenamic acid in bile was 1.1±0.3% of the dose, whereas the recovery of total 14C was 18.6±4.9%. The biliary clearances of tolfenamic acid and total 14C were 1.2±0.3 and 5.0±2.1 ml/min, respectively. Thus, biliary excretion plays a considerable part in the pharmacokinetics of tolfenamic acid.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00542174
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    A “once a day administration” sustained-release theophylline formulation: Disposition and pharmacokinetics (1984)
    Springer
    European journal of clinical pharmacology 27 (1984), S. 325-328 
    Details
    ISSN: 1432-1041
    Keywords: theophylline ; sustained release ; pharmacokinetics ; chronic administration ; healthy volunteers ; plasma levels ; GCMS assay ; stable isotope technique
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of a new sustained-release preparation of theophylline (Dilatrane à Action Prolongée capsules filled with homogenous microgranules) has been after its studied administration to 7 healthy volunteers at 8 p.m. in order to achieve therapeutic levels at night and in the morning. In separate trials the test dose of 500 or 600 mg was administered for 7 days, once daily at 8 p.m. Plasma theophylline levels were measured by capillary gas chromatography with a mass specific detector after pentylation, using internal standards labelled with stable isotopes (15N-1,3 and 13C-2 theophylline). The new sustained-release preparation showed a monophasic regular absorption phase with very low interindividual variability. After administration, the plasma level stayed within 80% of the peak levels for 8.5±1.5 h. There was a good correlation between the dose and the steady state plasma level (r=0.9587; p〈0.05). This preparation can be chronically administered once daily day at 8 p.m. in order to achieve a therapeutic level during the night and the morning, and to provide sufficient protection during the nycterohemeral period, with a once dose a day schedule.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00542169
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  • 177
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    Pharmacokinetics of high doses of piretanide in moderate to severe renal failure (1984)
    Springer
    European journal of clinical pharmacology 27 (1984), S. 589-593 
    Details
    ISSN: 1432-1041
    Keywords: piretanide ; renal insufficiency ; furosemide ; pharmacokinetics ; loop diuretic
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of piretanide was studied in 10 patients with chronic renal failure. After administration of a high oral dose (12 to 192 mg) of piretanide the kinetics behaved according to an open 2-compartment model. The elimination constant in the first phase (α) ranged from 0.385 to 0.756 h−1 and in the second phase (β) from 0.079 to 0.274 h−1. The corresponding elimination half-lives ranged from 55 to 108 min (t1/2 α) and from 152 to 524 min (t1/2 β). Only an average of 2.8% of the orally administered drug was recovered in 24 h urines. Nevertheless, a good correlation was found between urinary recovery or renal clearance of the drug and residual renal function. The elimination of piretanide by non-renal mechanisms appeared to be increased when renal function was greatly diminished.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00556897
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  • 178
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    DNA methylation in maternal, fetal and neonatal rat tissues following perinatal administration of procarbazine (1984)
    Springer
    Journal of cancer research and clinical oncology 108 (1984), S. 56-59 
    Details
    ISSN: 1432-1335
    Keywords: DNA methylation ; Rat ; Procarbazine
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The cytostatic drug procarbazine has previously been shown to be a potent transplacental neurotropic carcinogen in rats. Following a single IP administration of (14C-methylprocarbazine (110 mg/kg) on day 22 of gestation, methylation products with cellular DNA were determined in fetal and maternal rat organs. The concentration of the major adduct N7-methylguanine was highest in the maternal liver (224 μmol/mol guanine). Fetal and nonhepatic maternal tissues exhibited significantly lower levels, but differed little from each other. In brain, lung, intestines, and placenta the O 6-methylguanine/N7-methylguanine ratio was close to 0.11, indicating that procarbazine, like other methylating carcinogens, initiates malignant transformation via methyldiazonium hydroxide as the ultimate reactant. Following a single dose of (14C-methyl)procarbazine to newborn animals, methylpurine values were 30–60 times lower than after prenatal administration. This suggests that DNA alkylation in nonhepatic tissues occurs by systemic distribution of a proximate carcinogen formed in the adult rat liver.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00390973
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  • 179
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    Tumors of the nasal cavities induced in rats by 2,2-dioxopropyl-N-Propylnitrosamine (1984)
    Springer
    Journal of cancer research and clinical oncology 108 (1984), S. 114-120 
    Details
    ISSN: 1432-1335
    Keywords: Nasal cavities ; Rat ; DOPN
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Weekly SC administration of 2,2-dioxopropylnitosamine to 88 Sprague-Dawley rats resulted in the induction of 76 separate neoplasms in the respiratory region of the nasal cavities. No tumors of the olfactory region were found. Histologically there were 37 squamous papillomas, 17 transitional papillomas, and 22 squamous cell carcinomas. These tumors were compared with a selected group of 53 related human tumors of the nasal and paranasal cavities, consisting of 11 squamous cell papillomas, 13 transitional papillomas, and 29 squamous cell carcinomas. While the experimental squamous cell papillomas showed a striking histological resemblance with the squamous papillomas observed in man, none of the experimental transitional papillomas had evidence of the characteristics inverted pattern seen in humans: nevertheless, the experimental tumors showed signs of incomplete squamous metaplasia and preservation of intraepithelial secretory glands, features commonly seen in transitional papillomas of man. The squamous cell carcinomas of this experiment were very similar to the corresponding human tumors in morphology and sex incidence. In both species a significant number of squamous cell carcinomas were keretinizing and of a high grade of histological malignancy. In addition, 69% of the human squamous cell carcinomas occurred in the male sex, and 72% of the experimental carcinomas developed in males. This comparative study suggests that further studies investigating the significance of nitrosamines as suspected etiologic factors of nasal carcinogenesis in man may be useful.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00390982
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  • 180
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    The effects of exposure to diazepam during various stages of gestation or during lactation on the development and behavior of rat pups (1984)
    Springer
    Psychopharmacology 83 (1984), S. 51-55 
    Details
    ISSN: 1432-2072
    Keywords: Diazepam ; Prenatal ; Early postnatal treatment ; Learning disabilities ; Hyperactivity ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract In the present study we have investigated the effects of diazepam (DZP) (10 mg/kg) treatment of rat dams during different periods of gestation or during lactation on the development and behavior of their offspring. The results show that DZP exposure during different phases of early development has differing effects on later behavior. Exposure during mid-gestation resulted in early and transient hyperactivity, but no learning or memory deficits at 2 months of age were observed. However, both late prenatal and early postnatal exposure to DZP resulted in significant behavioral changes. Late prenatal treatment caused no hyperactivity but resulted in poor performance on the learning and retention of a choice discrimination task, while early postnatal exposure resulted in consistent and lasting hyperactivity and in substantial discrimination learning and retention deficits at 2 months of age.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00427422
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    Acquisition of behaviourally augmented tolerance to ethanol and its relationship to muscarinic receptors (1984)
    Springer
    Psychopharmacology 83 (1984), S. 88-92 
    Details
    ISSN: 1432-2072
    Keywords: Ethanol ; Behaviourally augmented tolerance ; Physiological tolerance ; Muscarinic receptor ; Operant conditioning ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Two groups of adult male rats were injected daily with ethanol (1.5 g/kg IP in 15% w/v solution) either before (the behaviourally augmented tolerant group) or after (the physiologically tolerant group) being placed in operant chambers. The control groups received daily isotonic saline injections either before or after the operant task. When challenged with ethanol (2.5 g/kg) on day 30 prior to the operant task, the control group was most impaired, while the behaviourally augmented tolerant group was significantly less impaired than the physiologically tolerant group. The two ethanol-treated groups were impaired to the same extent when challenged on day 60. Partial generalization of this behavioural tolerance to ethanol was observed, as the behaviourally augmented tolerant group was less impaired than the physiologically tolerant group for a tail flick response to painful stimuli after an ethanol challenge on day 30. However, the two ethanol-treated groups exhibited similar impairments of locomotor activity after an ethanol challenge on day 40. No differences in muscarinic receptor binding among the control and two ethanol-treated groups were found. These findings demonstrate that behaviourally augmented tolerance to ethanol may be partially generalizable but is unrelated to changes in muscarinic cholinergic receptors.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00427429
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  • 182
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    Interscapular brown adipose tissue blood flow in the rat (1984)
    Springer
    Pflügers Archiv 401 (1984), S. 414-417 
    Details
    ISSN: 1432-2013
    Keywords: Brown adipose tissue ; Microspheres ; Noradrenaline ; Rat ; Regional blood flow ; Xenon clearance
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The xenon clearance method was adapted to continuous measurement of interscapular brown adipose tissue (ISBAT) blood flow in anaesthetized rats. The ISBAT-blood partition coefficient for xenon was determined to 3.6 ml·g−1. The blood flow values obtained by Xe clearance were compared with flow values obtained concomitantly by the microsphere technique in 17 cold acclimated rats, at ISBAT blood flows between 0.1 and 6 ml·g−1·min−1. Variations in blood flows were obtained by infusion of noradrenaline at different rates. The blood flow values obtained from the xenon clearance method showed a close correlation to the blood flow values determined with microspheres.Y=0.98.X+0.15 (r=0.96,P〈0.001). The Xe clearance method has the advantages compared to the microsphere technique that it permits continuous monitoring of the blood flow and does not require the sacrifice of the animal.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00584345
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  • 183
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    A note on the rôle of generalized inverse Gaussian distributions of circulatory transit times in pharmacokinetics (1984)
    Springer
    Journal of mathematical biology 20 (1984), S. 95-102 
    Details
    ISSN: 1432-1416
    Keywords: pharmacokinetics ; generalized inverse Gaussian distribution ; recirculatory model ; renewal theory
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Mathematics
    Notes: Abstract Based on a stochastic pharmacokinetical model (which mirrors topological properties of the circulatory system) it is shown by reinterpreting results of Wise (1974) that if the transit times of circulating drug molecules have a generalized inverse Gaussian distribution the corresponding residence times are gamma distributed. The condition that the probability of elimination of a drug molecule in a single circulatory passage is sufficiently small appears to be valid for most drugs. Thus theoretical evidence is given for fitting blood concentration-time curves following bolus injection of a single dose by power functions of time.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00275864
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  • 184
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    Antinociceptive effects of neonatal capsaicin in rats with adjuvant arthritis (1984)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 326 (1984), S. 248-253 
    Details
    ISSN: 1432-1912
    Keywords: Neonatal capsaicin ; Antinociceptive effects ; Adjuvant arthritis ; Substance P ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Rats were treated with capsaicin (50 mg/kg, SC) either on the second day or on the second and third days of life. A significant attenuation of the responses to noxious stimuli was obtained in the capsaicin treated animals as measured by the hot-plate or paw pressure tests but not by the tail-flick test. Furthermore, neonatal capsaicin produced a significant reduction of response in the formalin test. Capsaicin reduced the reaction latency in rats with adjuvant arthritis as measured by the hot-plate and paw pressure tests, though capsaicin did not alter the overall time course of the response to Freund's adjuvant. Capsaicin also attenuated the weight loss or the decreased ambulatory and rearing behaviour which occurred in the control animals with adjuvant arthritis. It is suggested that neonatal treatment with capsaicin may relieve the responsiveness to longlasting nociceptive stimuli by adjuvant in rats.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00505326
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  • 185
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    Drug-induced rhythmic burst activity of cerebellar neurons (1984)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 326 (1984), S. 227-232 
    Details
    ISSN: 1432-1912
    Keywords: Pentobarbital ; Benzodiazepine derivatives ; Cerebellar Purkinje cell ; Interposed nucleus cell ; Discharge pattern ; Rabbit ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The discharge of cerebellar neurons was investigated in the rabbit and the rat under the influence of pentobarbital, diazepam or medazepam. In the rabbit, these drugs are known to induce a rhythm ranging between 4 and 25 Hz in the red nucleus (RN) and the cerebellum (Cb). Purkinje cells (P cells) in the intermediate zone of the cerebellar cortex as well as neurons of the interposed nucleus (IPN) were found to discharge with burst patterns fully synchronized with the drug-induced RN rhythm. In contrast, P cells in the medial cerebellar zone responded to these drugs only with changes in their discharge rate. Since P cells of the intermediate longitudinal zone project to the RN mainly via the IPN, the present findings complement our previous results, indicating that the rhythmic electrical activity in the RN is initiated by the cerebellum. The three drugs had similar effects on the activity of cerebellar units in the rabbit and the rat. The investigation also shows that, in spite of the uniform morphological structure of the cerebellar cortex, P cells do not respond uniformly to a given drug: the diversity of findings published on the P cell response to barbiturates or benzodiazepine derivatives may be explained by differences in the recording sites.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00505323
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    Role of muscarinic cholinergic mechanisms in the substantia nigra pars reticulata in mediating muscular rigidity in rats (1984)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 327 (1984), S. 14-17 
    Details
    ISSN: 1432-1912
    Keywords: Bethanechol ; Electromyogram ; Substantia nigra pars reticulata ; Morphine ; Muscular rigidity ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Bethanechol chloride (5–25 μg), when injected into the substantia nigra pars reticulata (SNR) of rats, produced muscular rigidity in a dose-dependent way, and in addition, catalepsy and ipsilateral posture. The effects of bethanechol in the dose of 25 μg were prevented by coadministration of 10 μg scopolamine hydrochloride. Injections of 25 μg betanechol or 10 μg scopolamine into the reticulata only slightly affected the muscular rigiditiy produced by 15 mg/kg i.p. morphine hydrochloride. The results suggest that muscarinic cholinergic mechanisms in the substantia nigra pars reticulata, although effective by themselves, affect by expression of at least one striatal functional alteration, the muscular rigidity, in a less effective way than GABAergic or endogenous opioid mechanisms do.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00504985
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  • 187
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    Lectin-binding properties of the Merkel cell and other root sheath cells in perinatal rat vibrissae (1984)
    Springer
    Cell & tissue research 236 (1984), S. 373-381 
    Details
    ISSN: 1432-0878
    Keywords: Merkel cell surface ; Quinacrine fluorescence ; Lectins ; Vibrissae ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Summary Surface carbohydrates on the Merkel cell of the outer root sheath (ORS) were investigated in 1to 4-day-old rat vibrissae by use of rhodamine isothiocyanate (RITC)-conjugated lectins. The red fluorescence of RITC provided a convenient assay for lectin binding to the Merkel cell, which is itself identified by its green fluorescence following selective uptake of the dye quinacrine. In monolayers or suspensions of freshly dissociated ORS cells, the Merkel cell showed high affinity for the α-fucose-specific lectin, Ulex europeus agglutinin I (UEA-I), thus revealing a novel feature for a basally located cell. Other high-affinity lectins included concanavalin A (Con A), wheat germ agglutinin (WGA), soybean agglutinin (SBA), and Ricinus communis agglutinin I (RCA-I). In contrast, Dolichos biflorus (DBA), Bandeiraea simplicifolia I and II (BS-I and BS-II), and peanut agglutinin (PNA) virtually excluded the Merkel cell, though PNA-binding sites were unmasked after neuraminidase treatment. Other dispersed ORS cells had varying lectin affinities, and generally binding was inhibited by a competing haptenic sugar. The pattern of lectin binding seen in cryostat and paraffin sections of the vibrissa suggested that the Merkel cells share surface properties with their neighboring basal and/or spinous cells; however, unshared properties are likely to exist since ingrowing mechanosensory nerves recognize the Merkel cells, and not other epidermal cells, as their targets.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00214241
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    Administration of caerulein to rats promotes antral epithelial cell renewal (1984)
    Springer
    Cell & tissue research 236 (1984), S. 711-715 
    Details
    ISSN: 1432-0878
    Keywords: Gastric antral mucosa ; Caerulein ; Gastrointestinal hormones ; Cholecystokinin ; Trophic effect ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Summary The growth-promoting effect of caerulein on antral gastric mucosa was explored using Wistar rats. Implanted osmotic minipumps were used to administer submaximal doses of either caerulein or saline to normal rats for up to 4 days. In one group, reflux of bile and pancreatic juice into the stomach was avoided by previous surgical diversion of the distal common bile duct to the jejunum. DNA synthetic and mitotic activity in the antrum epithelium were estimated by 3H-thymidine pulse labelling and autoradiography during the administration of the peptide. The rate of cell migration was determined in animals killed 1, 2 and 3 days after the 3H-thymidine pulse. Administration of caerulein to normal rats provoked significant increases in both labelling and mitotic indices, and a significant acceleration of the upward cell migration in the glandular tubes. In the animals with distal diversion of bile and pancreatic secretions both labelling and mitotic indices were also increased over control values under the effect of the peptide. These data indicate that administration of caerulein stimulates cell proliferation in the antral gastric mucosa. This effect cannot be explained through increased reflux of pancreaticobiliary secretions in the stomach.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00217242
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  • 189
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    Morphometric studies on lipid inclusions in Sertoli cells during the spermatogenic cycle in the rat (1984)
    Springer
    Cell & tissue research 236 (1984), S. 699-709 
    Details
    ISSN: 1432-0878
    Keywords: Testis ; Spermatogenic cycle ; Sertoli cell ; Lipid ; Morphometry ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Summary The volume and surface area of lipid inclusions often present in the cytoplasm of rat Sertoli cells was measured directly from semi-thin sections of perfusion-fixed testicular tissues using an image analyser linked to a light microscope. Sertoli cell nuclei were used as a reference for comparing any variations in the measured parameters of lipid inclusions during the rat spermatogenic cycle. Volume density of Sertoli cell lipid inclusions was assessed by morphometric analysis of Sertoli cells photographically reconstructed from electron micrographs. Maximum lipid content in Sertoli cells occurred during stages IX–XIV of the spermatogenic cycle, then declined at stages I–III and remained low from stages IV–VIII. The persistence and increase in number of many large Sertoli cell lipid inclusions beyond the stage where spermatid residual bodies are phagocytosed within the Sertoli cells (stage IX) suggests that the synthesis and lipolysis of Sertoli cell lipid inclusions represents an intrinsic functional cycle of the Sertoli cells. Stage-dependent variations in the lipid content of rat Sertoli cells offers morphological evidence that the metabolic duties of the Sertoli cells are synchronised with the spermatogenic cycle to provide local coordination of the proliferation and maturation of the germ cells.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00217241
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  • 190
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    The ovarian follicle as a model for the cell-mediated control of tissue growth (1984)
    Springer
    Cell & tissue research 236 (1984), S. 717-724 
    Details
    ISSN: 1432-0878
    Keywords: Ovary ; Ovarian follicle ; Atresia ; Immunoregulation ; Immune tolerance ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Summary Thy-1+ cells, producing Thy-1+ material, have been demonstrated by the indirect immunoperoxidase technique in the theca of growing ovarian follicles of the rat. OX-2 antigen, known as the minor glycoprotein of rat thymocytes, was detected in granulosa cells of non-growing follicles. Ia+ cells of dendritic type and/or activated macrophages were identified in the granulosa of advanced degenerating follicles, and remnants of the zona pellucida exhibited immunoglobulins. In some ovaries immunoglobulins were also bound to the zona pellucida of oocytes of early degenerating antral follicles. Medium-sized antral follicles with degenerating granulosa were occasionally invaded by cells carrying antigens of cytotoxic T lymphocytes or other T lymphocyte subsets, while degenerating large antral follicles were sometimes invaded by cells exhibiting antigen of cells with natural killer function (but not antigens of T lymphocytes). Granulosa cells of some degenerating antral follicles exhibited class-I antigens derived from the major histocompatibility complex. We suggest that cell-mediated control mechanisms of antigen expression and metabolism of tissue cells during their differentiation and degeneration should be considered in addition to the well-documented hormonal dependence of some tissues.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00217243
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  • 191
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    Glial cells in the pineal gland of mice and rats (1984)
    Springer
    Cell & tissue research 237 (1984), S. 245-252 
    Details
    ISSN: 1432-0878
    Keywords: Pineal organ ; Interstitial cells ; Astrocytes ; Immunocytochemistry ; Rat ; Mouse
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Summary Antigenic markers characteristic of astrocytes and their differentiative states (i.e., glial fibrillary acidic protein (GFAP), vimentin, and M1 and C1 antigens) were investigated in the pineal gland of mouse and rat using double immunolabeling techniques. In both species the socalled interstitial cells as characterized by TEM were shown to be astrocytes, since they expressed vimentin, but neither fibronectin (a marker for fibroblasts and endothelial cells) nor the neuron-specific L1 antigen or tetanus toxin receptors. Subpopulations of vimentin-positive pineal astrocytes were also GFAP- and C1- antigen-positive. M1- antigenpositive cells were not detected. It is concluded that a considerable proportion of interstitial cells in the pineal gland of rat and mouse are immature astrocytes which, in contrast to other parts of the central nervous system, persist into adulthood.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00217142
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  • 192
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    Evidence for a role of the cytoskeleton in the in vitro folliculogenesis of the thyroid gland of the fetal rat (1984)
    Springer
    Cell & tissue research 237 (1984), S. 499-508 
    Details
    ISSN: 1432-0878
    Keywords: Thyroid gland, fetal ; Cytoskeleton ; Cytocha lasin B ; Vinblastine ; Colchicine ; Follicular development (thyroid) ; Tissue culture ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Summary Thyrotropic hormone (TSH) or cAMP accelerate the formation of follicular cavities in the explanted thyroid gland of the 15-day-old rat fetus. Cytochalasin B or vinblastine and nocodazole or colchicine, which disorganize microfilamental and microtubular structures respectively, inhibit or completely block in vitro-induced folliculogenesis. Exposure of the thyroid tissue to lumicolchicine, a structural isomer of colchicine deprived of antimicrotubular activity, does not inhibit the activation of folliculogenesis induced by TSH. These results are strong evidence for the supposition that microfilaments and microtubules are involved in the TSH-stimulated mechanisms resulting in thyroid folliculogenesis. Folliculogenesis requires the integrity of both microfilaments and microtubules.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00228434
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  • 193
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    Immunohistochemical study on the development of CRF-containing neurons in the hypothalamus of the rat (1984)
    Springer
    Cell & tissue research 238 (1984), S. 539-544 
    Details
    ISSN: 1432-0878
    Keywords: CRF-neurons ; Hypothalamus ; Development, ontogenetic ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Summary Appearance of immunoreactive corticotropin-releasing factor (CRF)-containing neurons was studied in developing hypothalamus of the rat by use of antisera against rat- and ovine CRF. These neurons were first recognized in the lateral and paraventricular nuclei on days 15.5 and 16.5 of gestation, respectively, when antiserum against rat CRF was employed. Antiserum against ovine CRF revealed the cells two days later exclusively in the latter nucleus. In both nuclei, the neurons increased in number with development. The neurons in the paraventricular nucleus appeared to project their immunoreactive processes to the median eminence via the periventricular and lateral pathways. In the median eminence, the immunoreaction with antiserum to rat CRF was first recognized in its anterior portion in the form of dots on day 16.5 of gestation but as beaded fibers in the external layer on day 17.5; these structures increased in amount with development in rostro-caudal direction. Although antiserum to ovine CRF was less potent in immunostainability than antiserum to rat CRF, it also revealed the beaded fibers in the median eminence on day 17.5 of gestation. Since evidence is available that the paraventricular nucleus is involved in corticotropin release, it is concluded that, in rats, the hypothalamic regulatory mechanism controlling the release of corticotropin initially appears on days 16.5–17.5 of gestation.
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    URL: http://dx.doi.org/10.1007/BF00219870
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    Electronic Resource
    Immunocytochemical demonstration of caldesmon (a calmodulin-binding, F-actin-interacting protein) in smooth muscle fibers and absorptive epithelial cells in the small intestine of the rat (1984)
    Springer
    Cell & tissue research 235 (1984), S. 207-209 
    Details
    ISSN: 1432-0878
    Keywords: Caldesmon ; Actin ; Immunocytochemistry ; Small intestine ; Smooth muscle ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Summary The distribution of caldesmon (a calmodulin-binding, F-actin-interacting protein) (Sobue et al. 1982) and of actin was studied in the rat's small intestine by means of light-microscopic immunocytochemistry. Positive immunostaining for caldesmon was seen in smooth muscle cells of the intestinal wall, and of blood vessels, and in the apical portion of the absorptive epithelial cells. The immunoreactivity in goblet cells was difficult to recognize. The positive reaction to immunostaining for actin showed almost the same pattern as that for caldesmon. These results suggest that this calmodulin-binding protein may play an important role in the control of actin-myosin interaction in smooth muscle cells and in non-muscle cells.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00213742
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  • 195
    Electronic Resource
    Electronic Resource
    Internalization of ferritin-concanavalin A by the lactating mammary cell in vivo (1984)
    Springer
    Cell & tissue research 235 (1984), S. 433-438 
    Details
    ISSN: 1432-0878
    Keywords: Mammary gland ; Ferritin-concanavalin A ; Concanavalin A ; Endocytosis ; Membrane reuse ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Summary Ferritin-concanavalin A (Fer-Con A) was used to label the apical plasma membrane of the lactating cell to determine whether membrane internalization takes place. Rat glands were infused in vivo via the teat with 0.2 mg of Fer-Con A in 0.2 ml tris buffer (pH 7.0) containing 0.1% trypan blue, the latter acting as a marker of the infusate. Tissues were obtained from separate animals 5, 10 and 60 min postinfusion. Fer-Con A was seen in alveolar lumina bound to the outer surfaces of apical plasma membrane, microvilli and milk fat globules. It was observed within lactating cells on the inner membrane surfaces of endocytotic vesicles, Golgi cisternae, and secretory vesicles containing casein micelles, and in multivesicular bodies and lysosomes. Internalization of the ferritin-lectin conjugate into casein-containing secretory vesicles was detectable in the 5-min postinfusion tissue. Lysosomes were the only structures in control tissue that contained particles bearing some resemblance to Fer-Con A. The data provide evidence that apical plasma membrane is internalized and distributed to a number of intracellular compartments.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00217870
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  • 196
    Electronic Resource
    Electronic Resource
    Suprachiasmatic nucleus: Numbers of synaptic appositions and various types of synapses (1984)
    Springer
    Cell & tissue research 235 (1984), S. 449-452 
    Details
    ISSN: 1432-0878
    Keywords: Suprachiasmatic nucleus ; Morphometry ; Synapses ; Sexual dimorphism ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Summary The suprachiasmatic nucleus (SCN) of male rats was estimated to contain 16×106 synaptic appositions (unilaterally) or 250×106 appositions in 1 mm3 tissue of the nucleus with an average of 1404 appositions per neuron. There are significantly fewer synaptic appositions in the suprachiasmatic nucleus of female rats (15×106 per SCN or 236×106 in 1 mm3 tissue of SCN with 1264 appositions per neuron on an average). Additionally, numbers of various types of synapses (axo-somatic, invaginated, dendrodendritic and optic) are estimated.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00217872
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  • 197
    Electronic Resource
    Electronic Resource
    Regional effect of monosodium-L-glutamate on the superficial layers of superior colliculus in rat (1984)
    Springer
    Cell & tissue research 235 (1984), S. 453-457 
    Details
    ISSN: 1432-0878
    Keywords: Monosodium-1-glutamate ; Neuropathology ; Rat ; Superior colliculus ; Toxicology
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Summary Systemic administration of monosodium-1-gluta-mate by single injections of 4 mg/g body weight in infant rats (2–10 days of age) results in acute swelling of cytoplasm and nuclear pyknosis of neurons in the stratum zonale and stratum griseum superficiale of the superior colliculus. Multiple daily doses of 4 mg/g body weight monosodium-1-glutamate result in an almost complete loss of neurons in these two superficial layers. The deeper layers appear not to be affected. No pathological effects were observed in the lateral geniculate body or pretectal complex. Light-and electron-microscopic studies reveal that the optic nerves are remarkably shrunken and many myelinated as well as unmyelinated axons are lost. Injection of 3Hproline into the vitreous body of one eye results in limited transport to the suprachiasmatic nucleus, lateral geniculate body and to lateral portions of the superior colliculus. The small percentage of intact axons in the optic nerve, as well as the limited proline transport from the eye, suggest that administration of monosodium-1-glutamate leaves intact some optic fibers, a portion of which belongs to the retinohypothalamic tract.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00217873
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  • 198
    Electronic Resource
    Electronic Resource
    Electron-microscopic demonstration of the distribution of calcium deposits in the exocrine pancreas of the rat after application of carbachol, atropine, cholecystokinin, and procaine (1984)
    Springer
    Cell & tissue research 235 (1984), S. 683-690 
    Details
    ISSN: 1432-0878
    Keywords: Exocrine pancreas ; Calcium pool ; Calcium release ; Electron microscopy ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Summary In an attempt to identify a cellular Ca2+-pool, from which calcium is released when secretagogues are applied, tissue fragments of the rat exocrine pancreas were incubated and fixed with glutaraldehyde in the presence of calcium. By means of this procedure electron-dense deposits were found on plasma membranes. X-ray microanalysis showed that these deposits contain calcium. Stimulation of tissue fragments with the use of the secretagogues carbachol or cholecystokinin reduced the number of deposits by about 80%. When the antagonist atropine was applied after carbachol stimulation, deposits reappeared on cell membranes, which then disappeared again after a second stimulation with cholecystokinin. In the presence of procaine, carbachol was inhibited and only slightly reduced the Ca2+-deposits on the plasma membranes. These results suggest that a calcium pool, from which calcium is released to induce enzyme secretion on stimulation, is located in the cell membrane
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00226969
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  • 199
    Electronic Resource
    Electronic Resource
    Ontogenetic appearance of somatostatin-containing nerve terminals in the median eminence of rats (1984)
    Springer
    Cell & tissue research 236 (1984), S. 47-51 
    Details
    ISSN: 1432-0878
    Keywords: Somatostatin ; Ontogenesis ; Electron-microscopic immunohistochemistry ; Median eminence ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Summary The development of immunoreactive (ir) somatostatin-containing nerve terminals in the rat median eminence (ME) has been examined electron-microscopically. Nerve fibers containing ir particles scattered throughout the axoplasm are first seen in the external layer of the ME on day 18.5 of gestation, and, on day 21.5 appear to terminate on the basement membrane of the perivascular space of the portal vessels. After birth, the fiber terminals contain several membrane-limited granules, which are labeled with ir PAP particles. Ultrathin, Epon-embedded sections of ME, treated by the protein A gold-labeling method for somatostatin, demonstrate positively labeled granules in the nerve fibers in the postnatal ME, but in the prenatal tissue, no specific gold-labeling is found. These findings show that, in the external layer of the ME, somatostatin storing occurs in the granules in the axonal terminals after birth.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00216512
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  • 200
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    Electronic Resource
    Identification of pericytes in the central nervous system by silver staining of the basal lamina (1984)
    Springer
    Cell & tissue research 236 (1984), S. 491-493 
    Details
    ISSN: 1432-0878
    Keywords: Brain vessels ; Basal lamina ; Pericytes ; Endothelial cells ; Glial cells ; Argyrophilic staining ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Summary Vibratome sections obtained from perfusion-fixed rat brains were stained by means of silver impregnation and physical development according to Gailyas (1970). Small pieces of the cerebral cortex were postfixed with buffered osmium tetroxide solution and processed for electron microscopy to examine the localization of the silver deposit at the cellular level. The cell surfaces of pericytes and smooth muscle cells were completely outlined by silver grains. Endothelial cells and perivascular astrocytes, however, showed an asymmetric distribution of the silver deposit, i.e., the deposit was restricted to the abluminal endothelial surface and to the astrocytic membrane adjacent to the vessel wall, respectively. The method allowed a clear-cut distinction between perikarya of endothelial cells and pericytes as well as glial cells in perivascular position, even at the light-microscopic level.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00214255
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