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  • pharmacokinetics  (156)
  • Drosophila  (47)
  • NDE  (40)
  • Turbellaria
  • Springer  (279)
  • American Association for the Advancement of Science
  • 2010-2014
  • 1980-1984  (279)
  • 1935-1939
  • 1930-1934
  • 2010
  • 1982  (116)
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  • 2010-2014
  • 1980-1984  (279)
  • 1935-1939
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  • 1
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    Journal of molecular evolution 18 (1982), S. 310-314 
    ISSN: 1432-1432
    Keywords: Neutral mutation theory ; Natural selection ; Protein evolution ; Levene model ; Environmental variability ; Genetic variability ; Drosophila
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary If a phenotypic character is under stabilizing selection, the selective disadvantage of a nonoptimal genotype will decrease exponentially to zero as the proportion of phenotypic variation that is environmental in origin -V e /V p - increases. Under the modified mutation-drift hypothesis of genetic polymorphism, the proportion of mutations that are effectively neutral and average heterozygosity should increase with this ratio. Invertebrates, because of their small size, fast development, and low degree of homeostasis (relative to vertebrates), are expected to show a larger environmental component of phenotypic variation than vertebrates. This may help explain why invertebrates are in general more genetically variable than vertebrates and why, when laboratory populations ofDrosophila are maintained in heterogeneous environments, genetic variability is lost less rapidly than when they are kept in constant conditions.
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  • 2
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    Development genes and evolution 191 (1982), S. 285-288 
    ISSN: 1432-041X
    Keywords: Drosophila ; Imaginal discs ; homoeosis ; Compartments ; Aldehyde oxidase
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary The aldehyde oxidase staining pattern in wing discs ofDrosophila melanogaster bearing the genotypesap blt /ap blt andap blt andap blt /ap 73n showns changes from the wild-type pattern. Extensive areas of the presumptive dorsal posterior wing blade, which are normally unstained, have enzyme activity in these mutants. In wings of these genotypes, dorsal posterior structures are replaced by dorsal anterior wing structures. A strong correlation has been found between the frequencies of various staining patterns in the discs and the extent of transformation in the cuticular structures of the wing, which is consistent with the idea that aldehyde oxidase activity can be used as an indicator in the wing disc of this transformation. Unlike the homoeotic mutationengrailed, apterous has not been interpreted as a selector gene yet the work reported here shows thatapterous alleles can cause changes resembling those of theengrailed phenotype both in aldehyde oxidase staining behaviour and in the cuticular transformation.
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  • 3
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    Development genes and evolution 191 (1982), S. 264-269 
    ISSN: 1432-041X
    Keywords: Drosophila ; Sexcombless ; Foreleg basitarsus ; Genital disc
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary The chromosome which carries the mutationsexcombless (In(1)sx) affects males and females ofD. melanogaster. In the male foreleg basitarsi the number of sexcomb teeth is dramatically reduced from 10 to 0.7 and the number of transverse rows of bristles is increased from 6 to 8. Females homozygous forIn(1)sx show a normal bristle pattern in the foreleg basitarsus. The genital disc derivatives of both male and femaleIn(1)sx flies are strongly affected. While the external genitalia show a duplicated or a reduced bristle pattern, the internal genitalia are mostly absent. However, the sexually dimorphic tergites and sternites of the abdomen remain unaffected. The male-specific effect on the basitarsus and the general effects on the genital disc derivatives are proposed to represent two different phenotypic effects ofIn(1)sx which may derive from mutations at different gene loci in the inverted chromosome.
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  • 4
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    Development genes and evolution 191 (1982), S. 289-291 
    ISSN: 1432-041X
    Keywords: Drosophila ; Imaginal discs ; Cell competition
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary Imaginal wing discs from late third-instar larvae were gammairradiated to induce clones of rapidly growingMinute − cells in a background of slowly growingMinute cells and culturedin vivo for periods up to 18 days. Clones in discs cultured for 16 to 18 days did not grow significantly larger than clones in uncultured controls, indicating that competition between populations of cells having potentially different mitotic rates does not occur in imaginal discs after their growth is completed.
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  • 5
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    Development genes and evolution 191 (1982), S. 103-111 
    ISSN: 1432-041X
    Keywords: Drosophila ; Polytene Chromosomes ; Ecdysteroids ; Fat Body
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary Changes in polytene chromosome 3 L puffing patterns in the fat body ofDrosophila melanogaster larvae and prepupae are compared to those in the salivary gland. While some general features are common to the two tissues, there are differences which reflect their different developmental roles. In vitro experiments with fat body chromosomes show that they have a distinct response to ecdysteroids which is different from that of salivary gland chromosomes, and which does not,in this culture system, reproduce the changes observed in normal development. In short term culture experiments, the fat body chromosomes appear more sensitive to ecdysteroids than the salivary gland chromosomes and, although 20-OH ecdysone is more active than ecdysone in these assays, the possibility is not excluded that ecdysone has a role in normal development as it appears to alter gene activity at physiological levels in these cells.
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  • 6
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    Development genes and evolution 191 (1982), S. 293-300 
    ISSN: 1432-041X
    Keywords: Drosophila ; Imaginal discs ; Positional information ; Homology ; Intercalary regeneration
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary The regulative behavior of fragments of the imaginal discs of the wing and first leg was studied when these fragments were combined with fragments of other thoracic imaginal discs. A fragment of the wing disc which does not normally regenerate when cultured could be stimulated to regenerate by combination with certain fragments of the haltere disc. When combined with a haltere disc fragment thought to be homologous by the criteria of morphology and the pattern of homoeotic transformation, such stimulated intercalary regeneration was not observed. Combinations of first and second leg disc fragments showed that a lateral first leg fragment could be stimulated to regenerate medial structures when combined with a medial second leg disc fragment but not when combined with a lateral second leg disc fragment. Combinations of wing and second leg disc fragments showed that one fragment of the second leg disc is capable of stimulating regeneration from a wing disc fragment while another second leg disc fragment fails to stimulate such regeneration. It is suggested that absence of intercalary regeneration in combinations of fragments of different thoracic imaginal discs is a result of homology or identity of the positional information residing in the cells of the fragments. The pattern of correspondence of positional information revealed by this analysis is consistant with the pattern of homology determined by morphological observation and by analysis of the positional specificity of homoeotic transformation among serially homologous appendages. The implications of the existence of homologous positional information in wing and second leg discs which share a common cell lineage early in development are discussed.
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  • 7
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    Development genes and evolution 191 (1982), S. 335-339 
    ISSN: 1432-041X
    Keywords: Drosophila ; Gap junction ; Wing disc
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary The distribution of gap junctions in mature larvalDrosophila melanogaster wing discs was analyzed by means of quantitative electron microscopy. Gap junctions are non-randomly distributed in the proximal-distal disc axis and in the apical-basal cell axis of the epithelium. In the epithelial cells, the surface density, number and length of gap junctions are greatest in the apical cell region and distal disc region. The average gap junction surface density is 0.0572 μm−1 and 2.77% of the lateral cell surface is composed of gap junctions. In the adepithelial cells, the gap junction surface density is 0.0005 μm−1 and 0.06% of the cell surface is composed of gap junctions. No gap junctions were observed between epithelial cells and adepithelial cells. The absolute area of gap junctions was estimated in a proximal-distal strip of cells in the disc and is considerably less in the folded regions of the epithelium compared to the flat notum and wing pouch regions. The results are discussed with respect to pattern formation and growth control in imaginal discs.
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  • 8
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    Development genes and evolution 191 (1982), S. 28-36 
    ISSN: 1432-041X
    Keywords: Drosophila ; Polarity ; Maternal effect ; Nurse cells ; Embryogenesis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary The mutationdicephalic (dic) affects follicle development and thereby alters the antero-posterior polarity of embryonic patterning. It maps at a single locus (3–46.0±1.0) and can be characterized as a semi-dominant maternal effect mutation with low penetrance. Indic follicles, the 15 nurse cells form two clusters located at opposite poles of the oocyte; the numerical distribution of the nurse cells among the clusters varies from 7:8 to 1:14. Thedic egg shell carries a micropyle (anterior marker) at either pole, but the misshapen respiratory appendages are restricted to one of the two poles in most eggs. The malformed eggs rarely yield larvae and these are always abnormal anteriorly and/or posteriorly. The segment pattern expressed in their cuticle may represent two anterior parts of opposite polarities (double head type), two posterior parts of opposite polarities (double abdomen type, rare) or show uniform polarity. Lability of organization at the cystocyte stage appears as the primary developmental defect of the mutant.
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  • 9
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    Development genes and evolution 191 (1982), S. 42-55 
    ISSN: 1432-041X
    Keywords: Clonal analysis ; Growth ; Cell lineage ; Genital disc ; Drosophila
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary InDrosophila, the terminalia (i.e. internal and external analia and genitalia, except the gonads) are formed by the genital disc. Comparative studies suggested that this disc may have evolved through fusion of the imaginal primordia of the last 3 or 4 abdominal segments. The present report describes the clonal relationships within the complex genital disc. Genetically marked cell clones were induced in male and female embryos and larvae heterozygous for cell marker mutations. 1) Frequencies and sizes of clones suggest that the embryonic disc anlage consists of 14–17 precursor cells: 4–6 for the analia, some 7 for the male genitalia, and 3–4 for the female genitalia. These cells grow exponentially during larval development. 2) In both sexes, the clones were confined to either analia or genitalia, suggesting two separate cell lineages already established at blastoderm. 3) Internal and external genitalia remain in the same compartment at least up to 60 h (end of first instar). 4) A clonal restriction appeared around 84 h (mid second instar), separating a dorsal from a ventral part in the male genitalia. The ventral compartment comprises the ventral part of the lateral plate and clasper, hypandrium, and all internal genitalia. No such boundary was detected in the female. 5) In the female, analia and parovaria originate from the same precursors; another cell lineage forms eighth tergites, vaginal plates, oviduct, receptacle, and spermathecae. 6) In female analia, dorsal and ventral plate share common precursors at least up to 84 h. A medio-lateral boundary may appear at 84 h in the ventral anal plate. No clonal restriction was found in the male analia. 7) At all times, clones could cross between left and right sides of the symmetrical terminalia; they consistently did so via ventral structures. 8) The results are discussed in a phylogenetic context, and we propose that the clonal relations reflect the evolution of the complex genital disc.
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  • 10
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    Development genes and evolution 191 (1982), S. 191-201 
    ISSN: 1432-041X
    Keywords: Neurogenic mutants ; Maternal effects ; Drosophila
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary The size of the neurogenic region ofDrosophila melanogaster is under the control of several genes of zygotic expression. Lack of function from any of those genes produces an increase of the size of the neurogenic region at the expense of the epidermal anlage. However, differences exist in the extent of neuralisation achieved by each of the genetic loci upon mutation. The present results show that in the case ofN andmam phenotype differences are due to different contributions of maternal gene expression. This could be shown by studying the phenotype which appeared in mutant embryos when the oocytes developed from homozygous mutant precursor cells. Clones of mutant cells were induced in the germ line of females heterozygous for the neurogenic mutationin trans over germ line dependent, dominant female sterile mutations. After removing maternal information the phenotype ofN andmam mutants became identical in both cases. Furthermore maternal information fromN + was found to be necessary for viability of the wildtype.
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  • 11
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    Development genes and evolution 191 (1982), S. 211-214 
    ISSN: 1432-041X
    Keywords: Drosophila ; Clonal analysis ; Sex determination
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary The mutationSxl f , located on the X-chromosome, is a sex-limited recessive lethal that specifically kills 2X; 2A flies while it does not affect X; 2A flies (Cline 1978). We have analyzed the role ofSxl f on sex determination by a clonal analysis of a new spontaneous allele,Sxl fLS . Female embryos and larvae heterozygous forSxl fLS were irradiated at different times of development to generate homozygousSxl fLS clones which were recognized by linked marker mutations. We have studied the phenotype of such clones on sexually dimorphic regions of the fly (foreleg basitarsus, 5th, 6th and 7th tergites, analia and external genitalia). Despite their female (2X; 2A) chromosomal constitution, clones homozygous forSxl fLS differentiated male structures. These results confirm and extend the preliminary report of Cline (1979). They show that the wildtype product ofSxl f is required for female development.
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  • 12
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    European journal of clinical pharmacology 21 (1982), S. 287-291 
    ISSN: 1432-1041
    Keywords: tolmesoxide ; hypertension ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Tolmesoxide is a new, direct-acting vasodilator drug for use in the management of both hypertension and cardiac failure. In 6 essential hypertensives inadequately controlled by combined β-blocker and diuretic therapy (average supine blood pressure 178/103 mm Hg) the addition of tolmesoxide (300–900 mg daily) was associated with a significant improvement in blood pressure control (average supine blood pressure 161/89 mmHg). The effect of food on the pharmacokinetics and pharmacodynamics of tolmesoxide have also been studied because, particularly at higher doses, the drug has been associated with upper gastrointestinal upset and it has been empirically recommended that it be taken with food. The blood pressure and heart rate responses were not significantly different when tolmesoxide was taken fasting or with food. Food resulted in a significant reduction in the peak plasma tolmesoxide concentration (2.14 µg/ml compared to 2.97 µg/ml) and a significant increase in the time to reach peak plasma concentration (1.67 h compared to 0.63 h). Although there was no impairment of its hypotensive effect, food significantly altered the pharmacokinetics of tolmesoxide and may therefore be useful in reducing the gastrointestinal disturbance associated with its use. In the treatment of inadequately controlled hypertension, tolmesoxide has a limited role as an alternative vasodilator.
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  • 13
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    European journal of clinical pharmacology 21 (1982), S. 307-310 
    ISSN: 1432-1041
    Keywords: piretanide ; renal failure ; high dose ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The kinetics of piretanide was studied in patients with renal failure. After oral administration of a high dose of piretanide (96 mg), the pharmacokinetic parameters were: elimination rate constant 0.346±0.072 h−1, half life 2.00±0.35 h, and total plasma clearance 119.55±35.90 ml · min−1. Compared to the values obtained in adults with normal renal function, these results show a decrease in total plasma clearance, but conservation of the metabolic clearance which amounts to 45% of the total clearance in the healthy adult.
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  • 14
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    European journal of clinical pharmacology 21 (1982), S. 397-402 
    ISSN: 1432-1041
    Keywords: ergotamine ; migraine ; radioimmunoassay ; clinical effects ; adverse effects ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The systemic availability of ergotamine after a single therapeutic oral or rectal dose was studied using a radioimmunoassay during the headachefree state in 24 patients suffering from migraine. Plasma concentrations of the drug were compared with anamnestic data about its clinical effects in the same patients. Among 12 patients with a good therapeutic response to medication, the mean plasma ergotamine levels stayed in the range 0.20 to 0.50 ng/ml for 6h. Their mean plasma levels at 30 min (0.33ng/ml) and 1h (0.40ng/ml) were significantly higher than those (0.06 and 0.08ng/ml, respectively) in 9 patients with only a moderate therapeutic response. In 9 patients with a moderate and 3 with a poor therapeutic response, the mean plasma level generally stayed below 0.10ng/ml. The mean peak concentrations in moderate (0.13 ng/ml) and poor (0.11ng/ml) responders appeared later (at 3h) than in good responders (at 1h). Side effects of the medication appeared to be associated with relatively low plasma levels of ergotamine and also with delayed maximum plasma concentrations of the drug. The present results suggest that the time of the maximum plasma drug level is an important determinant of the clinical effects of ergotamine, and that a good therapeutic response may be expected if a plasma ergotamine level of 0.20ng/ml or more is achieved within 1 hour after oral or rectal administration.
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  • 15
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    European journal of clinical pharmacology 21 (1982), S. 343-350 
    ISSN: 1432-1041
    Keywords: orphenadrine ; single dose ; multiple doses ; bioavailability ; pharmacokinetics ; N-demethylorphenadrine ; metabolism ; dog ; man
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Plasma concentrations of orphenadrine were measured by a specific gaschromatographic method in 5 healthy male volunteers after a single oral dose of orphenadrine hydrochloride 100mg. The single dose pharmacokinetic profile of orphenadrine was evaluated from these data. The elimination half-life ranged from 13.2–20.1 h after the commercial tablet formulation. Plasma concentrations, determined in volunteers and patients under different conditions of repeated oral administration of the same formulation of orphenadrine hydrochloride exceeded the theoretical values, predicted from the single dose pharmacokinetics, by a factor 2 to 3. The elimination half-lives after discontinuation of treatment showed a 2 to 3-fold increase over the single dose values. This demonstrates a clear discrepancy between the multiple and single dose pharmacokinetics of orphenadrine. Experiments in dogs suggested competition for biotransformation between orphenadrine and its metabolite N-demethylorphenadrine. Product inhibition of this type could explain the observed discrepancy.
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  • 16
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    European journal of clinical pharmacology 22 (1982), S. 273-279 
    ISSN: 1432-1041
    Keywords: amoxycillin ; i.v. administration ; pharmacokinetics ; two- and three-compartment models
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetic characteristics of amoxycillin were studied in healthy volunteers after intravenous injection of 250 mg, 500 mg and 1,000 mg, and infusion of 2 g and 5 g. Serum concentrations were fitted using either bi- and tri- exponentional equations. Comparison of the regression curves obtained revealed that the three-compartment model gave a better fit to the serum concentration versus time curve. It was evident that there was a third, slow, dose dependent phase of disposition. This result has been confirmed by the fact that the terminal half life of amoxycillin on cessation of a continuous infusion is significantly greater than after acute administration.
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  • 17
    ISSN: 1432-1041
    Keywords: indapamide ; bioavailability ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Two formulations of indapamide tablets (2.5 mg) were given as a 5.0 mg dose and the subsequent blood levels were compared to those obtained after administration of a 5.0 mg solution. The study was conducted as a randomized three-way crossover design using healthy male volunteers. The drug was well tolerated by all the subjects involved. The area under the blood concentration versus time curve, extrapolated to infinity was essentially the same for all three formulations (4.2, 4.7, and 4.4 µg-h/ml). Statistical comparison of the blood levels from the two tablets showed that one tablet had a significantly greater maximum blood concentration (263 vs 231 ng/ml) and a significantly shorter time of maximum blood concentration (2.3 vs 3.5 h). Cmax (333 ng/ml) and tmax (0.7 h) values for the solution were significantly higher than either tablet. The average half-life (β-phase) for all three formulations was 15 h, while the average systemic clearance was 20 ml/min. Indapamide has a low clearance rate and there was no evidence that the drug undergoes a first-pass effect.
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  • 18
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    European journal of clinical pharmacology 22 (1982), S. 257-264 
    ISSN: 1432-1041
    Keywords: TRIS buffer ; metabolic acidosis ; pharmacokinetics ; cellular uptake ; renal excretion ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary To investigate the pharmacokinetics of TRIS, an infusion of the buffer was given to 6 healthy volunteers (121 mg/kg=1 mmol/kg; pH 7.4) and to 20 patients suffering from metabolic acidosis (109–376 mg/kg; pH 10.9). The drug exhibited two-compartment characteristics in volunteers (t0.5,β=5.6 h) and patients with intact renal function (t0.5,β=16.3–45.6 h). The final volume of distribution (Vβ) indicated uptake into tissues, but equilibration between body compartments was slow. Mainly unchanged TRIS was eliminated by the kidney; 82% of the administered dose was recovered from 24 h-urine of healthy subjects. In the patients a linear correlation between creatinine-clearance and TRIS-clearance was observed, the latter always being somewhat greater than the former. Only insignificant amounts of the drug were found in bile and gastric juice. In anuric patients the plasma concentration of TRIS declined monoexponentially, with a half-life between 10 and 58 h. Haemodialysis or haemofiltration did not influence this process. From the data it seems questionable whether cellular uptake of TRIS is an important factor in the therapy of intracellular acidosis, but the possibility of drug accumulation must be borne in mind if repeated doses are given to the same patient.
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  • 19
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    European journal of clinical pharmacology 23 (1982), S. 75-80 
    ISSN: 1432-1041
    Keywords: psoriasis ; 8-methoxypsoralen ; food influence ; suction blister fluid ; serum ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The influence of food on the kinetics of 8-methoxypsoralen (8-MOP) in serum and suction blister fluid was evaluated in a cross-over study in 19 psoriatic patients under PUVA treatment. The peak serum concentration of 8-MOP was reached 1.5 h after ingestion on an empty stomach, and in suction blister fluid the maximum concentration was already present in the first sample taken after 2 h, the time when UVA radiation was given. The postprandial kinetics of 8-MOP in serum and suction blister fluid differed, the highest levels being reached, respectively, at 2.4 and 3 h after intake, i.e. in both body fluids after irradiation had started. The side effects of 8-MOP, such as nausea and dizziness, in the two groups were similar. The present results indicate that to optimize the therapeutic effect of PUVA in individual patients, 8-MOP should be given on an empty stomach.
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  • 20
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    European journal of clinical pharmacology 23 (1982), S. 189-195 
    ISSN: 1432-1041
    Keywords: befunolol ; propranolol ; pharmacokinetics ; pharmacodynamic effects ; beta-adrenoceptor blocking agent
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Repeated doses of a new β-adrenoceptor blocking agent, befunolol, were administered orally to adult male volunteers for a cross-over comparison with propranolol. The β-adrenoceptor blocking activity of befunolol was greater than that of propranolol when assessed by the percentage reduction in exercise-induced tachycardia. The elimination half-life of drug was significantly prolonged on repeated administration of propranolol, but not of befunolol. The percentage reduction in exercise-induced tachycardia was highly correlated with the log plasma level of each drug. Both drugs produced a significant reduction in pre-exercise systolic and diastolic blood pressure, and significant attenuation of exercise-induced rise in systolic blood pressure.
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  • 21
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    European journal of clinical pharmacology 23 (1982), S. 235-240 
    ISSN: 1432-1041
    Keywords: ergotamine ; pharmacokinetics ; migraine ; plasma drug levels ; i.v. administration ; i.m. administration ; bioavailability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The kinetics of ergotamine has been investigated in migrainous patients using a new, specific, sensitive HPLC assay (detection limit 100 pg/ml plasma). 10 patients were given ergotamine tartrate 0.5 mg i.v. and 5 of them received the same dose i.m. 2–3 weeks later. Blood samples were collected for up to 54 h following administration and the plasma concentration were analysed. After intravenous administration the plasma ergotamine declined rapidly, with an initial distribution half-life of 3 min followed by a mean terminal half-life of 1.86 h (range 90–155 min). The mean total plasma clearance was 11.0 ml kg−1 min−1, and the volume of distribution (Vdβ ) was 1847.6 ml kg−1. Individual t1/2β showed a positive linear correlation with the individual Vdβ . The intramuscular absorption of ergotamine was rapid and maximum plasma levels were usually obtained 10 min following administration. The biological availability was incomplete and variable at 46.6% (range 28.3–60.8%).
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  • 22
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    European journal of clinical pharmacology 23 (1982), S. 327-330 
    ISSN: 1432-1041
    Keywords: bendroflumethiazide ; cantharides plasters ; blister fluid ; plasma levels ; pharmacokinetics ; compartmental analysis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of bendroflumethiazide (BFT) was investigated following the oral administration of 10 mg to 3 healthy volunteers. Each subject participated twice in the study. BFT was determined in plasma and cantharides blister fluid from 1/2 to 30 h post administration. Blister fluid was obtained from blisters 10–22 h old. Plasma levels were fitted to a tri-exponential equation and the concentration of the drug in the peripheral compartment was calculated from the microscopic rate constants. In 5 of 6 cases investigated, cantharides blister fluid levels paralleled the concentration of the drug in the peripheral compartment. The mean blister fluid levels exceeded the calculated concentration in Compartment 2 1.46 fold. In one case, the blister fluid level paralleled the plasma level. This subject clearly differed from the others as more than 10 h were required for blister formation in her. The results suggest that following the administration of BFT, cantharides blister fluid behaves as part of the peripheral compartment. The possible value of studying blister fluid levels in pharmacokinetic investigations is discussed.
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  • 23
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    European journal of clinical pharmacology 23 (1982), S. 343-347 
    ISSN: 1432-1041
    Keywords: valproic acid ; fatty acids ; plasma protein binding ; pharmacokinetics ; drug metabolism
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effect of physiologic variations of free fatty acid levels on in vivo valproic acid plasma protein binding was studied in 6 healthy adult subjects. 14 blood samples were taken during a 12-h dosing interval at steady state while in a fed condition and also during a 27 h fast. Free fraction and total valproate concentration were determined by equilibrium dialysis and GLC, respectively. Free fatty acid levels were determined from both fresh samples and samples incubated at 37°C for 12 h, the latter in order to simulate equilibrium dialysis conditions. Fasting resulted in increased serum free fatty acid levels in all subjects, ranging from 34–182% (p〈0.01). Incubation also caused free fatty acid levels to rise, more so in fed samples (50–87%,p〈0.01) than in fasting samples (10–50%,p〈0.01). Fasting resulted in a 9% increase in the mean free fraction for all subjects combined (p〈0.01). Regression analysis of 180 sets of values for free fraction, total valproate concentration and free fatty acid level suggested that valproate concentration accounts for 17% and free fatty acid level for 37% of the variation in free fraction. Mean clearance was unchanged by fasting despite an increased free fraction suggesting decreased intrinsic clearance (i.e. decreased metabolism) of valproate under these conditions.
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  • 24
    ISSN: 1432-1041
    Keywords: L-threo-3,4-dihydroxyphenylserine ; familial amyloid polyneuropathy ; pharmacokinetics ; norepinephrine ; pressor response
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of oralL-threo-3,4-dihydroxyphenylserine (L-threo-DOPS) was studied in 7 normal subjects and 7 patients with familial amyloid polyneuropathy. Each person swallowed a single 300 mg dose in the fasting state, andL-threo-DOPS in plasma and urine was determined by high performance liquid chromatography with an electrochemical detector after separation on a boric acid gel column.L-threo-DOPS was slowly absorbed by normal subjects; the maximum plasma concentration occurred 3 h after administration and 20% of the oral dose was recovered unchanged in the urine within 12 h. It induced a substantial elevation of plasma norepinephrine levels, the peak being attained at 5 h, but without any change in blood pressure. In the patients, the absorption and metabolism ofL-threo-DOPS were delayed, and a prolonged pressor response was observed, with a peak after 8 h. It was concluded that the effects on plasma norepinephrine and blood pressure of oralL-threo-DOPS were essentially equal to those of twice as large a dose ofDl-threo-DOPS.
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  • 25
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    European journal of clinical pharmacology 23 (1982), S. 501-504 
    ISSN: 1432-1041
    Keywords: cimetidine ; uraemia ; dosing regimen ; prediction ; computer program ; old age ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Using a recently developed computer program based on a correlation between methods to predict the elimination half-life and apparent volume of distribution of cimetidine and actual data from patients, ideal dosage regimens were generated for patients with renal impairment and for geriatric patients, together with the corresponding maximum and minimum steady state concentrations. Using the ideal dosage regimens, practical regimens with feasible dosing intervals of 6, 8 and 12 h were computed, which should result in therapeutic concentrations of 0.4 to 1.3 µg/ml. For uraemic patients and geriatric patients above the age of 75 years it would be desirable to have an additional oral 100 mg dosage form.
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  • 26
    ISSN: 1432-1041
    Keywords: amitriptyline ; imipramine ; clomipramine ; antidepressant overdose ; clinical effects ; pharmacokinetics ; cardiotoxicity ; maprotiline ; doxepine ; nortriptyline ; opipramol
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Twenty-nine cases of self-poisoning with antidepressants (amitriptyline, imipramine, clomipramine, maprotiline, doxepine, nortriptyline, opipramol) were examined by frequent observation of CNS effects, heart rate, blood pressure and standard ECG, 24 h-ECG-monitoring, measurement of systolic time intervals, EEG recordings and frequent measurement of serum levels of antidepressants and primary metabolites. None of the patients died. Maximum total serum antidepressant level (parent compound + desmethyl metabolite) ranged from 20 to 2200 µg/l, with concentrations above 500 µg/l in 11 cases. The serum amitriptyline concentration remained high for 3–4 days in some of the severely intoxicated patients and the decay curves were compatible with partly saturated elimination. A degree of unconsciousness and the occurrence of excitation and hallucinations were generally seen in cases with total serum antidepressant levels above 500 µg/l. Grand mal seizures occurred more frequently at high antidepressant levels, but could not be predicted from the EEG recordings. Increased heart rate and prolonged QRS- and QTc-intervals were significantly correlated with the total serum antidpressant level. 24 h-ECG-monitoring revealed no serious arrhythmias or instances of heart block. Hypotension was only seen initially in few patients. Systolic time interval measurements showed changes suggesting impaired myocardial performance (elevated PEP/LVET ratio) at intermediate (60–500 µg/l) but not high (〉500 µg/l) total serum antidepressant levels. Measurement of serum concentration in antidepressant intoxication is important for identification of patients with high serum levels and the corresponding risk of developing toxic reactions, and to exclude patients with a low concentration who do not require intensive observation.
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  • 27
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    European journal of clinical pharmacology 23 (1982), S. 1-5 
    ISSN: 1432-1041
    Keywords: clonidine ; noradrenaline ; pharmacokinetics ; arterial blood pressure ; plasma concentration
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of clonidine and its relation to blood pressure response and side effects were studied after single oral doses of 75 µg, 150 µg and 250 µg in normotensive subjects. Following oral administration, the drug was absorbed rapidly after an initial lag time of 19–22 min and peak levels were reached between 2.4 and 2.9 h. Sampling over 48 h was necessary for accurate estimation of pharmacokinetic parameters. Post-peak plasma concentration declined in a monoexponential manner and the half-life of the elimination phase ranged from 9.0 to 15.1 h. Maximum plasma concentration (Cmax) and area under curve (AUC) increased proportionally with increasing doses. Clonidine produced significant reductions in the pulse rate and a dose dependent decrease in blood pressure. Clonidine (150 µg) also produced significant reductions in plasma catecholamine levels.
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  • 28
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    European journal of clinical pharmacology 23 (1982), S. 43-47 
    ISSN: 1432-1041
    Keywords: timolol ; pharmacokinetics ; pharmacodynamics ; healthy subjects ; cardiac infarction patients ; i.v. therapy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Disappearance pharmacokinetics, pharmacodynamics and general tolerance of i.v. timolol were compared in 12 healthy volunteers and 10 patients with a definite or proven acute myocardial infarction. The drug was administered to the patients immediately on arrival at the hospital after a median delay time of 4 h. Tolerance to the injections was good in both volunteers and patients. The study revealed disappearance pharmacokinetics that were similar in volunteers and patients.
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  • 29
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    European journal of clinical pharmacology 21 (1982), S. 293-301 
    ISSN: 1432-1041
    Keywords: metipranolol ; deacetyl metipranolol ; pharmacokinetics ; bioavailability ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetic parameters of deacetyl metipranolol were determined after i.v. infusion of increasing doses (6–25 mg) in 17 normal volunteers. In a second cross-over trial, deacetyl metipranolol 10 and 20 mg were infused in a further 10 subjects, and in a third trial another 20 volunteers received metipranolol 40 mg orally. Metipranolol is very rapidly and completely deacetylated in man, so all pharmacokinetic data refer to deacetyl metipranolol, which was assayed by gas chromatography-mass spectrometry. The pharmacokinetic analysis was performed using a recently developed model, using a volume of distribution which is variable with time. The following data were obtained after oral administration: (mean values); lag-time 7.3 min; tmax 50 min, invasion half-life 6.3 min; elimination half-life 3 h; urinary excretion of unchanged drug approximately 4% of the dose. The experiments with infusion of increasing doses, as well as the cross-over study with 10 and 20 mg i.v., showed dose-linearity of the kinetics. The respective mean half-lives of elimination were 2.6, 2.9 and 2.8 h. The mean total, renal and extra-renal clearances amounted to 1237 ml/min, 149 ml/min and 1068 ml/min, respectively. The distribution coefficient was 3.5 l/kg, and protein binding amounted to 70% within the range of therapeutic concentrations. Absolute bioavailability was found to be approximately 50% by several different evaluation procedures. Thus, the pharmacokinetic profile of metipranolol shares features of both the lipophilic and the hydrophilic groups of β-blocking agents.
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  • 30
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    European journal of clinical pharmacology 21 (1982), S. 315-323 
    ISSN: 1432-1041
    Keywords: bendroflumethiazide ; propranolol ; hydralazine ; pharmacokinetics ; thin-layer chromatography ; fluorimetry ; fixed combination product
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Bendroflumethiazide (Bft) was administered to 6 healthy subjects at 3 different dose levels (2.5, 5 and 10 mg) in a cross-over design, either as capsules (2.5 mg) or as tablets (5 mg). Its pharmacokinetics were evaluated then and following administration of a fixed combination of Bft with propranolol and hydralazine to a further 7 volunteers. Plasma and urinary concentrations of Bft were determined by a new fluorimetric — thin-layer chromotography procedure. Peak plasma levels occurred after 2–3 h and averaged 15, 27 and 45 µg/l in the three dose groups. Areas under the plasma concentration — time curves (AUC0→12), which were 75, 147 and 250 µg l−1 h respectively, and cumulative urinary recovery (20%) were independent of the dose administered and the type of formulation. Thus Bft kinetics proved to be linear within the dose range evaluated. The plasma clearance was calculated to be 505 ml/min, renal clearance 108 ml/min and nonrenal clearance 396 ml/min. Bioavailability of Bft was not altered following administration of the fixed combination. The amount of propranolol found in the circulation did not change, whereas that of hydralazine (determined as apparent hydralazine) increased by 59% when the fixed combination was administered.
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  • 31
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    European journal of clinical pharmacology 21 (1982), S. 421-425 
    ISSN: 1432-1041
    Keywords: benzodiazepine ; lormetazepam ; lormetazepam glucuronide ; transfer to milk ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The concentrations of lormetazepam and its glucuronide in plasma and milk were determined during administration of 10 daily doses of lormetazepam 2 mg (2 tablets of NOCTAMID® - 1) to five mothers delivered by Caesarian section. Their babies were breast-fed throughout the study, and the plasma levels of lormetazepam and its glucuronide were determined three times in the babies. At 12 and 24h after administration, the plasma level of lormetazepam was about 3.5 ng/ml and 1.8 ng/ml in mothers, and below 0.09 ng/ml in the children. In milk the lormetazepam concentration was below 0.2 ng/ml. The plasma level of glucuronide varied between 24 ng/ml at 12h and 11 ng/ml 24h after administration. Almost no accumulation of unchanged lormetazepam was observed (factor: 1.3). The ratio of the levels of lormetazepam in milk and plasma was estimated to be below 0.06, and for the glucuronide the ratio was 0.04. The quantity of free and conjugated active ingredient transferred to the children via breast milk was calculated to be at most 100 ng/kg, corresponding to 0.35% of the maternal dose, which is regarded as tolerable.
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  • 32
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    European journal of clinical pharmacology 21 (1982), S. 499-504 
    ISSN: 1432-1041
    Keywords: gentamicin ; malnutrition ; pharmacokinetics ; infant
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of gentamicin was investigated in normal and malnourished infants aged 4–10 months. Neither mean “elimination” nor “distribution half life” show any difference, but the volume of distribution was higher in malnourished babies, probably due to their larger total body water.
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  • 33
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    European journal of clinical pharmacology 22 (1982), S. 423-428 
    ISSN: 1432-1041
    Keywords: pindolol ; renal failure ; metabolism ; pharmacokinetics ; 14C-pindolol ; blood metabolites ; urinary metabolites
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Increased metabolism of pindolol in renal impairment has previously been suggested by pharmacokinetic calculations. The present study was a pharmacokinetic and metabolic investigation in 7 patients with severe renal impairment (endogeneous creatinine clearance below 5 ml/min). All the patients received pindolol 5 mg t.d.s. 5 days. On the sixth day, after an overnight fast, 14C-pindolol 5 mg was given orally as a solution to drink. Blood samples were taken for up to 72 h and urine was collected at intervals up to 96 h for measurement of unchanged pindolol by a fluorimetric method and total radioactivity by liquid scintillation counting. Metabolites in blood and urine were analysed after separation by HPLC. It was found that the plasma levels following a single dose of 14C-pindolol were similar to those observed in healthy volunteers, but the elimination half-life was slightly increased up to 11.5 h. The observed steady state plasma concentrations of pindolol were twice as high but they are still in the therapeutic range of 10 to 100 ng/ml. Therefore, the dose of pindolol could have been reduced by a factor 2, but the reduction was not essential. No active metabolite of pindolol was found in plasma or urine, but elimination of the metabolites was decreased. The elimination half-life following multiple doses was prolonged compared to normal and it was quite comparable to that found for the pharmacodynamic half-life in renal patients. The discrepancy between the present findings and the previous results for metabolism and pharmacodynamic half-life was probably due to the sensitivity of the fluorimetric assay of pindolol.
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  • 34
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    European journal of clinical pharmacology 23 (1982), S. 155-160 
    ISSN: 1432-1041
    Keywords: amikacin ; pharmacokinetics ; development ; neonate ; infant ; child
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The disposition kinetics of a single i.v. dose of amikacin was studied in 6 neonates (6–25 days old), 10 infants (4–18 months) and 8 young children (3–11 years). There was a progressive change in the distribution and elimination kinetics during development. The distribution coefficient of the antibiotic averaged of 0.429, 0.320 and 0.210 l/kg in the newborns, infants and young children, respectively and serum half-life (t1/2 β) in these three groups averaged 2.812, 1.803 and 1.196 h, respectively. Significant differences in certain pharmacokinetic parameters were found between the values in paediatric patients and in adults receiving the same dose. A linear relationship was established between the distribution volume of the antibiotic and the weight of the patients, as defined by the following equation: $${\text{Vd}}_{{\text{ss}}} \left( 1 \right) = 0.976 + 1.140 \cdot {\text{TBW}}\left( {{\text{kg}}} \right);r = 0.954$$ The results suggest that a regimen of very frequent administrations should be employed in infants and young children in order to maintain a therapeutic level throughout treatment.
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  • 35
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    European journal of clinical pharmacology 22 (1982), S. 161-169 
    ISSN: 1432-1041
    Keywords: mebendazole ; hydatid disease ; Echinococcus granulosus ; hepatic disease ; pharmacokinetics
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The plasma concentrations of mebendazole and its metabolites have been monitored in twelve patients after receiving a 10 mg/kg dose for cystic hydatid disease. The mebendazole plasma concentration-time profiles differed considerably between patients; elimination half-lives ranged from 2.8–9.0 h, time to peak plasma concentration after dosing ranged from 1.5–7.25 h and peak plasma concentrations ranged from 17.5 to 500 ng/ml. The mean peak plasma concentration of mebendazole after an initial dose (69.5 ng/ml) was lower than found in patients during chronic therapy (137.4 ng/ml). The plasma AUCTs for the major metabolites of mebendazole (methyl 5-(α-hydroxybenzyl)-2-benzimidazole carbamate and 2-amino-5 benzoylbenzimidazole) were about five times the plasma AUCT found for mebendazole in patients on chronic therapy. It is suggested that the slower clearance of these polar metabolites relative to mebendazole results from enterohepatic recycling. Since mebendazole is also highly plasma protein bound, caution should be observed in administering mebendazole to patients with liver disease. Concentrations of mebendazole found in the tissue and cyst material collected from two patients during surgery ranged from 59.5 to 206.6 ng/g wet weight.
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  • 36
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    European journal of clinical pharmacology 23 (1982), S. 173-176 
    ISSN: 1432-1041
    Keywords: melperone ; neuroleptic drug ; dose dependent kinetics ; i.m. injection ; i.v. injection ; pharmacokinetics ; oral application
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of melperone (Buronil®, Ferrosan, Sweden) was studied after administration of various parenteral and oral doses to man. After parenteral administration, the data could be fitted to a two-compartment model, but after oral dosing the distribution phase could not be separated from the elimination phase, and so an one-compartment model gave the best fit. The half-lives were about 3–4 h, except after intramuscular injection, when the half-life was about 6 h. The bioavailability of oral doses was about 60% of the intravenous injection. After the highest oral dose of 100 mg, the pharmacokinetics, expressed as AUC or Cmax, showed non-linearity, possibly due to saturation of the hepatic elimination system.
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  • 37
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    European journal of clinical pharmacology 23 (1982), S. 331-333 
    ISSN: 1432-1041
    Keywords: ketoconazole ; vaginal candidosis ; oral antimycotic ; distribution ; pharmacokinetics ; vaginal tissue concentrations
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Plasma samples and biopsies of vaginal tissue were obtained from 23 healthy women undergoing operative sterilization, 1 to 6 h after a single oral dose of ketoconazole 200 mg. Drug concentrations in plasma and tissue, were measured by a specific gas chromatographic method. The vaginal tissue concentration averaged 2.4 times less than the corresponding plasma levels. Equilibrium between tissue, and plasma was established within 1 h after dosing, when vaginal tissue levels exceeded 1 µg/g. Ketoconazole concentrations decayed monoexponentially over the time interval studied (1–6 h), with the similar half-lives of 1.2 and 1.4 h in plasma and tissue, respectively. Following an oral 200 mg dose, a tissue concentration not less than 0.01 µg/ml was maintained over a 12 h period. This concentration has been shown to prevent outgrowth of the invasive (pseudo) mycelial form ofCandida albicans. Hence, a b.i.d. or t.i.d. dosage schedule of ketoconazole in vaginal candidosis would give continuously effective levels at the site of infection. Ketoconazole concentrations in vaginal fluid are thought to be much higher than in the tissue because of ion-trapping. The present data may explain the efficacy of oral ketoconazole in the treatment of vaginal candidosis.
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  • 38
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    European journal of clinical pharmacology 21 (1982), S. 303-306 
    ISSN: 1432-1041
    Keywords: furosemide ; renal failure ; haemodialysis ; pharmacokinetics ; children ; dosage schedule
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Furosemide was measured by gas-liquid chromatography in blood and dialysis fluid from 7 children with chronic renal failure, undergoing regular haemodialysis. It was administered chronically, in two or three daily doses (4.2–9.4 mg/kg). Two children received 1 mg/kg intravenously for determination of the pharmacokinetics. The half-life was longer than in adults and in anephric patients on haemodialysis. Systemic and renal clearance were also much lower. Plasma protein binding in 2 out of 6 cases was reduced as campared to normal adults. The data do not suggest any need to modify the present dosage schedule despite the 4–5 fold increase in the half-life of furosemide. The contribution of haemodialysis to drug clearance was minimal, and accounted for less than 10% of the total clearance.
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  • 39
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    European journal of clinical pharmacology 21 (1982), S. 331-334 
    ISSN: 1432-1041
    Keywords: diclofenac sodium ; rheumatoid disease ; healthy subjects ; serum albumin ; pharmacokinetics
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Pharmacokinetic data for diclofenac sodium has been well established in healthy volunteers, whereas in patients with rheumatoid arthritis very little information is available in the literature. A single oral dose of enteric-coated diclofenac sodium was given to 10 patients with active rheumatoid disease, adopting the same procedures used for a group of 10 healthy volunteers in whom pharmacokinetic data was already available. Plasma specimens were collected over a period of 8h following administration and concentrations of diclofenac determined by GLC. Resulting plasma concentration curves were similar to those obtained in the healthy subjects in that areas under curves and terminal half-lives were comparable. However, peak concentrations of diclofenac were significantly reduced in the rheumatoid patients. The lower peak concentrations were correlated with the lower serum albumin levels in the patients which are associated with active rheumatoid disease.
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  • 40
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    European journal of clinical pharmacology 22 (1982), S. 47-52 
    ISSN: 1432-1041
    Keywords: apnoea ; caffeine ; premature infants ; pharmacokinetics
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of caffeine was examined in 13 premature infants (gestational age 25–34 weeks, birth weight 920–2060 g, postnatal age 1–42 days) who received the drug for treatment of opnoea. Caffeine (1% aqueous solution) was given i.v. in single doses; guided by the clinical response infants received between one and seven (mean 2.6) doses of 15 mg/kg. Mean (± SE; range) Clb was extremely slow − 8.5 ml/kg/h (±0.4; 5.8–12.2), t1/2 was prolonged − 65.0 h (±3.7; 48.2–87.5 h) and Vd was 0.781/kg (±0.04; 0.47–1.01). No significant correlation was found between Clb, t1/2 and postnatal age in the whole group or in individual infants. Effective plasma concentrations varied over a wide range (12–36 µg/ml) and overlapped with subtherapeutic concentrations (⩽24 µg/ml). Single doses of 15 mg/kg i.v. or p.o. prevented apnoea in most cases, if necessary followed by additional doses. Monitoring the blood level of caffeine in infants receiving frequent repeated doses is necessary to prevent toxicity.
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  • 41
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    European journal of clinical pharmacology 22 (1982), S. 359-365 
    ISSN: 1432-1041
    Keywords: chlorpheniramine ; pharmacokinetics ; oral absorption ; half-life ; bioavailability ; volume of distribution
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Plasma and urinary levels of chlorpheniramine (CPM) and its 2 demethylated metabolites were measured by HPLC after i.v. and oral dosing. In 5 mg (maleate) i.v. bolus studies in 2 subjects, plasma CPM levels were fitted to triexponential equations with terminal half-lives (t 1/2) of 23 and 22 h and area of 3.6 and 3.21/kg, respectively. Intravenous data predicted hepatic blood extraction ratios for the 2 subjects to be 0.06 and 0.07, respectively. Absolute bioavailability from oral solution (10 mg) was 59 and 34%, and from tablets (8 mg) 44 and 25%, respectively, indicating extensive gut first-pass metabolism. Mean t 1/2 from 7 oral fasting studies in 5 subjects was 28 h (19–43 h). Mean absorption lag time was 0.7 h (0.4–1.3 h), and mean peak time was 2.8 h (2–4 h). In 2 subjects, 6 mg solutions were given every 12 h for 9 doses; good correlation between single and multiple dose kinetics was found. Significant accumulation was demonstrated in simulation studies with frequent daily dosing. Estimated accumulation ratios vary from 4.1 to 9.4 (mean 6.5). The t 1/2 from urinary data (collected for 12 days) was consistent with plasma data. The above results suggest the need to reexamine the current practice of frequent daily dosing and the use of sustained or controlled release dosage forms of this drug. The possible cause of reduced plasma clearance of CPM in renal patients is discussed.
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  • 42
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    European journal of clinical pharmacology 23 (1982), S. 93-97 
    ISSN: 1432-1041
    Keywords: tolmesoxide ; vasodilator ; hypertension ; pharmacokinetics ; haemodynamics ; plasma renin activity
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The haemodynamic response and pharmacokinetics of single dose oral tolmesoxide were studied at various dose levels in 4 patients with severe hypertension. There was a reproducible fall in mean arterial pressure from baseline of 24.2% and a rise in heart rate of 37.6% following administration of tolmesoxide. The onset of antihypertensive action occurred within 1 h, with a peak effect at 3 h after dosing. The mean duration of action was up to 12.0 h. Tolmesoxide had a mean half-life of 3.0 h. It was rapidly absorbed with a mean peak plasma level occurring at 1.0 h. Plasma levels correlated well with the doses administered. Side-effects included mild nausea, facial flushing and postural symptoms.
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  • 43
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    European journal of clinical pharmacology 23 (1982), S. 37-42 
    ISSN: 1432-1041
    Keywords: metoprolol ; propranolol ; oxprenolol ; pharmacokinetics ; acetubolol ; diacetolol ; oral contraceptive
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Plasma concentrations of metoprolol, propranolol oxprenolol, acebutolol and its metabolite diacetolol were measured after single oral doses in young healthy volunteers. In order to assess the inter-and intra-subject variability the following pharmacokinetic parameters were compared: AUC o 24 , Cmax, tmax and t1/2. The smallest variation in inter-subject variability was seen with oxprenolol and acebutolol: intrasubject variability was more uniform. Female volunteers taking an oral contraceptive generally had higher AUC o 24 and Cmax values than those not. This finding reached statistical significance only for metoprolol AUC o 24 .
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  • 44
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    European journal of clinical pharmacology 23 (1982), S. 49-57 
    ISSN: 1432-1041
    Keywords: verapamil ; norverpamil ; pharmacokinetics ; atrial fibrillation ; oral administration ; i.v. administration
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetic parameters and oral bioavailability of the antiarrhythmic drug verapamil were determined in six patients with atrial fibrillation. Plasma samples were taken following i.v. injection of verapamil 10 mg (Isoptin® 2 ml), and oral verapamil 80 mg (Isoptin® 2 tablets of 40 mg). Verapamil and its N-demethylated metabolite, norverapamil, were analyzed to 1 ng/ml plasma by gas chromatography-mass spectrometry using deuterated standards. Following intravenous injection, the disposition of verapamil followed a biexponential pattern with a fast distribution phase and a slower elimination phase (t1/2β=5.79 h), corresponding to a plasma clearance of 0.26 1/kg/h. After oral administration, only an elimination phase was evident, with the same elimination rate (t1/2β=5.53 h). The oral bioavailability was 10.5%±7.5%. The norverapamil formed after i.v. and oral administration of verapamil had plasma half-lives of 5.86 h and 6.77 h, respectively. The elimination of verapamil in patients with atrial fibrillation was decreased compared to that in healthy young volunteers and the oral bioavailability was lower. Very good correlation between the percentage reduction in heart rate and the log plasma concentration of verapamil was found in every patient during the elimination phase, irrespective of the route of administration. There was also a high correlation when the plasma concentration — effect data from all the patients were pooled (r=0.59,n=71;p〈0.0005).
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  • 45
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    European journal of clinical pharmacology 23 (1982), S. 123-127 
    ISSN: 1432-1041
    Keywords: theophylline ; bronchiolitis ; infants ; pharmacokinetics ; single dose ; multiple doses ; HPLC
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Theophylline pharmacokinetics were studied in 12 infants (age 3 weeks–6.5 months) with bronchiolitis. 9 of the 12 patients received a single dose of aminophylline (5.0–8.5 mg/kg) whereas the remainder were at steady-state receiving multiple doses (2.5–5.0 mg/kg) of aminophylline. The dose was administered IV over 0.5–1.0 h. An HPLC method was used to measure theophylline concentrations in serum and urine. Peak serum concentrations of theophylline measured by HPLC ranged from 8.48–21.6 µg/ml. Total, renal and nonrenal clearance of theophylline ranged from 4.66 to 19.25, 1.07 to 5.76 and 3.59 to 16.83 ml/min/m2, respectively. Mean apparent volume of distribution and elimination half-life were 8.75 l/m2 and 11.38 h, respectively. Although no significant correlation was observed between age and theophylline kinetic parameters, clearance appeared to increase and half-life decrease with age. Our patients had a substantially lower clearance and longer half-life as compared to published data in children 〉1 year of age. A five-fold variation in theophylline clearance demonstrates the need for monitoring theophylline serum concentration to minimize the risk of potential toxicity.
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    European journal of clinical pharmacology 23 (1982), S. 129-134 
    ISSN: 1432-1041
    Keywords: theophylline ; ethinylestradiol ; oral contraceptives ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effect of chronic oral contraceptive (OC) usage on the disposition of theophylline was examined. Aminophylline solution (4 mg/kg) was given orally to 8 healthy female non-OC users and to 8 healthy women who were chronic (〉6 months) OC users. The OC user group had a significantly lower total plasma clearance of theophylline than women not using OC (35.1±5.6 vs. 53.1±14.5 ml/h/kg). The t1/2 was also significantly prolonged in the OC group (9.79±1.43 vs. 7.34±1.75 h) while the volume of distribution was similar between the 2 groups. The serum ethinylestradiol (EE) concentrations after oral OC administration were measured simultaneously. The apparent clearance of EE was about 30% lower in the OC users. A significant positive correlation was found between the apparent clearance of EE and the plasma clearance of theophylline. The effects of OC are predominantly due to chronic use with decreased elimination of both theophylline and EE.
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  • 47
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    European journal of clinical pharmacology 23 (1982), S. 167-172 
    ISSN: 1432-1041
    Keywords: ticarcillin ; probenecid ; excretion ; pharmacokinetics ; automated chemical assay method
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The excretion of radioactivity has been investigated in 3 healthy volunteers following rapid intravenous administration of 5 g of [35S]-ticarcillin. The radioactive dose was rapidly and completely excreted, since within 4 days 98.5% was recovered, 95% in the urine and 3.5% in faeces. All the urine radioactivity was accounted for as ticarcillin and its penicilloic acid. Plasma and urine samples collected from the volunteers at frequent intervals during the first 6 h of the experiment were assayed for penicillin by an automated chemical method and also for radioactivity. The results obtained by the chemical autoanalyser method were in excellent agreement with the plasma levels of radioactivity. From the data it was possible to calculate the renal clearance of the penicillin, a mean value of 104 ml/min was observed in the 3 volunteers. A further three volunteers were dosed intravenously with a 5 g bolus of non-radiolabelled ticarcillin in a cross-over study with and without predosing with probenecid. Serum samples were analysed by the chemical method for penicillin and the data subjected to pharmacokinetic analysis using a two compartment open model. The results indicate a shift of the distribution equilibrium of ticarcillin from the serum into the peripheral compartment after predosing with probenecid. Furthermore, the mean half-life of ticarcillin in the serum of the three volunteers was significantly increased from 1.3 h to 2.1 h by predosing with probenecid.
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  • 48
    ISSN: 1432-1041
    Keywords: dipyridamole ; platelets ; plasma levels ; pharmacokinetics ; adenosine uptake
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Two preparations of dipyridamole have been studied by oral administration to 11 normal volunteers. The plasma levels of dipyridamole and its glucuronide were determined simultaneously by high performance liquid chromatography. The instant form (I.F., 100 mg) was administered four times daily and the slow release preparation (SRP, 200 mg) twice daily, for 3 days. Multiple blood samples were collected on Days 1–4 to provide plasma for assay, and simulteneously, platelet rich plasma was prepared for ex vivo study of the effect of dipyridamole on platelet uptake of adenosine. The pharmacokinetics of absorption and distribution of dipyridamole were described using a two compartment model with lag time and prolonged absorption. Strong inhibition of the platelet adenosine uptake was observed at therapeutic plasma levels. The inhibition of platelet adenosine uptake may be related to some of the pharmacological properties of dipyridamole.
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  • 49
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    European journal of clinical pharmacology 23 (1982), S. 349-351 
    ISSN: 1432-1041
    Keywords: indomethazine ; rheumatoid arthritis ; pharmacokinetics ; tolerance ; side effects ; slow-release tablets
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics, efficacy and tolerance of a new formulation of slow-release indomethacin tablet were compared with those of a conventional indomethacin capsule in 30 patients with rheumatoid arthritis. The slow-release tablet was absorbed more slowly than the capsule (tmax 3.7 h and 〈 2 h, respectively) and produced more even serum drug levels in 10 subjects. Side-effects, especially dizziness and diarrhoea, were less frequent after the slow-release tablet than during the capsule period.
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  • 50
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    European journal of clinical pharmacology 21 (1982), S. 335-341 
    ISSN: 1432-1041
    Keywords: phenylephrine ; pharmacokinetics ; bioavailability ; first-pass metabolism ; phenolic conjugates ; m-hydroxymandelic acid ; intravenous ; oral
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary 7-3H-phenylephrine was given to 15 volunteers by a short-infusionn=4) or p.o. (10 volunteers, 1 patient with porto-caval anastomosis). Analysis of serum for free3H-phenylephrine and fractionation of urinary radioactivity was performed by ion-exchange and thin-layer chromatography. As almost the same3H-activity was excreted in urine after i.v. and p.o. administration, 86% and 80% of the dose respectively, complete enteral absorption can be assumed. A considerable difference was seen in the fraction of free phenylephrine, i.v. 16% of the dose versus p.o. 2.6%, which suggested reduced bioavailability. This was confirmed by comparison of the areas under the serum curve, which showed a bioavailability factor of 0.38. The result for the patient with porto-caval anastomosis was comparable to that in the normal volunteers. The biological half-life of 2 to 3h was comparable to that of structurally related amines, as were the total clearance of 2 1/h, and the volume of distribution of 340l. Metabolism to phenolic conjugates mainly after oral ingestion, and tom-hydroxymandelic acid after i.v. injection, again demonstrated thatm-hydroxylated amines are predominantly conjugated during the “first-pass” metabolism.
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  • 51
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    European journal of clinical pharmacology 22 (1982), S. 315-320 
    ISSN: 1432-1041
    Keywords: furosemide ; cirrhotic patients ; ascitic fluid ; diuretic effect ; pharmacokinetics ; healthy volunteers
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of furosemide was studied in 7 patients with diagnosed liver cirrhosis and in 7 healthy subjects. Furosemide in plasma and ascitic fluid was analyzed spectrofluorometrically. After a single intravenous dose, the cirrhotic patients showed lower initial plasma concentrations of furosemide because of the larger volume of distribution. The mean half-life in cirrhotic patients was significantly greater than in healthy volunteers. The longer half-life was associated with a reduction in the serum clearance of furosemide. Ascitic fluid volume in the patients ranged from 4.6 to 7.71. There was no significant amount of furosemide in the fluid. The diuretic interchange between this fluid and plasma was slow, as peak concentrations ranged from 0.3 to 0.5 µg/ml within 3 to 5 h after bolus administration of furosemide. Diuresis and urinary sodium excretion, 5 h after furosemide injection, were similar in both groups; larger potassium excretion was found in the cirrhotic patients.
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  • 52
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    European journal of clinical pharmacology 21 (1982), S. 325-330 
    ISSN: 1432-1041
    Keywords: cimetidine ; renal failure ; cimetidine sulphoxide ; pharmacokinetics ; haemodialysis
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary A single intravenous dose of cimetidine 200mg was administered to 6 patients with severe chronic renal failure one hour prior to haemodialysis. The plasma concentrations of cimetidine and its sulphoxide metabolite at the start of haemodialysis were 2.74±0.12 and 0.76±0.08 µg/ml, and after dialysis for 4h 1.08±0.10 and 0.51±0.08 µg/ml, respectively (mean ± SE). The average haemodialysis clearance (ClHDa) of cimetidine during dialysis was 46–92ml/min at a dialysate flow rate of 320ml/min and blood flow rates in the 6 patients between 160–240ml/min. The mean ClHDa of the sulphoxide metabolite was 44% higher than that of cimetidine, and ranged between 49–148ml/min. During haemodialysis the mean plasma elimination half-life (t1/2) of cimetidine was 3.24h (range 2.08–5.08) and of the sulphoxide metabolite 9.49h (range 4.70–14.39). There was a significant relationship between the elimination rate constant (β) and ClHDa of the sulphoxide metabolite (p〈0.01), but no such relationship was found between β and ClHDa of cimetidine. However, there was a tendency to a relationship between β of cimetidine and the capacity to metabolise the drug, expressed as the ratio between the plasma concentrations of the sulphoxide metabolite and cimetidine after dialysis for 4h. These ratios ranged between 0.23–0.76, and the lowest ratio was seen in the patient with the lowest β value of cimetidine. Thus, the large variations in the plained by differences in their capacity to metabolise the drug. The mean total amount of cimetidine eliminated during dialysis was 27.3mg (range 17.9–31.8), which was 9.0–15.9% of the given dose. Between 12.2–21.2mg (mean 15.3) of the sulphoxide metabolite was eliminated in the dialysate. Major adjustment of the dose of cimetidine on days of dialysis is not necessary.
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  • 53
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    European journal of clinical pharmacology 21 (1982), S. 351-354 
    ISSN: 1432-1041
    Keywords: lithium ; plasma level decay curve ; elimination ; pharmacokinetics ; psychiatric patients
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Chronic treatment with conventional lithium carbonate was interrupted in a selected group of 40 psychiatric patients of mixed sex and race. All patients had normal renal function. Serum samples were taken 12, 24, 36 and 48 h after the last dose and lithium was assayed by atomic absorption spectrophotometry. Decay rates calculated for the 12–24 h and 36–48 h periods yielded different values. This was ascribed to the presence of an incomplete redistribution phase during the earlier period. The distribution of elimination rates determined during the later period gave a more symmetrical spread and approximated a normal distribution. The mode, median, mean and standard deviation of the lithium elimination half-lives were 12.5, 14, 18.2 and 7.3 h and 22.5, 24.5, 29.8 and 10.1 h for the two periods, respectively. The results contrast sharply with another report of the distribution spread of elimination half-lives in a much larger sample. The current values have implications for dosage prediction, serum level monitoring and dosage formulation, especially sustained-release preparations. The evidence was against the possibility that some individuals ‘retain’ lithium.
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  • 54
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    European journal of clinical pharmacology 21 (1982), S. 373-377 
    ISSN: 1432-1041
    Keywords: propranolol ; sotalol ; thyrotoxicosis ; bioavailability ; serum tri-iodothyronine ; pharmacokinetics
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The elimination and bioavailability of two beta-blocking agents, propranolol and sotalol, were studied in 10 thyrotoxic patients, both before and after treatment with iodine-131. Each subject received in random order propranolol 160 mg and sotalol 160mg as single oral doses both while hyperthyroid and after euthyroidism had been achieved. The pharmacokinetics of sotalol was not affected by hyperthyroidism, whereas serum propranolol concentrations were significantly lower during hyperthyroidism than in the euthyroid state. During hyperthyroidism, the bioavailability of propranolol was significantly reduced (p〈0.05) and its clearance was increased (p〈0.005), whereas there was no difference in its serum t1/2. This indicates that the bioavailability of propranolol in hyperthyroidism is reduced by a mechanism which may depend on increased first-pass metabolism in the liver, or on an increased distribution volume of the drug. Both propranolol and sotalol caused a slight decrease in serum tri-iodothyronine concentration. As the effects of beta-blocking agents on the symptoms of hyperthyroidism are correlated with the serum concentration of the drugs, sotalol, with its long half-life and unaltered elimination in hyperthyroidism, has certain advantages over propranolol in the treatment of thyrotoxicosis.
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  • 55
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    European journal of clinical pharmacology 21 (1982), S. 433-441 
    ISSN: 1432-1041
    Keywords: antipyrine ; antipyrine metabolites ; drug metabolism ; route of administration ; healthy volunteers ; urinary excretion ; pharmacokinetics
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of antipyrine in plasma and saliva, and urinary excretion of its major metabolites, were studied following i.v. and oral administration of antipyrine 500 mg to 6 healthy volunteers. Data from both plasma and saliva showed that the oral bioavailability of antipyrine given as an aqueous solution was complete. The saliva/plasma concentration ratio was constant with time from about 3 h onwards, with a mean value of 0.87 after oral and 0.91 after i.v. administration. It is concluded that the pharmacokinetic parameters of antipyrine can be satisfactorily established on the basis of salivary data, although the volume of distribution and clearance values are then slightly too high. After i.v. administration, 3.8±1.9% of the dose was excreted in urine as unchanged antipyrine in 48h, 24.9±6.3% as 4-hydroxyantipyrine, 16.5±3.2% as norantipyrine, 13.0±2.2% as 3-hydroxymethyl-antipyrine and 5.8±1.0% as 3-carboxy-antipyrine. No significant differences were observed following oral administration. The half-lives calculated from the linear part of the urinary excretion rate curves of the metabolites were about the same for oral and i.v. administration, and were of the same order of magnitude as the elimination half-life of parent drug in plasma and saliva. It is important for determination of the ultimate metabolite ratio that urine is collected for at least 36h, because there is a delay in the excretion of 3-hydroxymethyl-antipyrine in urine.
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  • 56
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    Keywords: clomipramine ; desmethylclomipramine ; depressive syndrome ; plasma level ; pharmacokinetics ; clinical response ; benzodiazepines
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Thirty one in-patients suffering from depression were treated orally with clomipramine (Cl) at various dosage, for 28 days, after a “wash-out” period of three days. In 17 patients receiving 75 mg per day of Cl, steady state plasma levels of Cl were reached at Day 14, and steady state plasma levels of its active metabolite, desmethylclomipramine (DMCl), were reached at Day 21. In contrast, in 7 other patients receiving a dosage increasing to 150 mg per day at Day 7, mean plasma levels of Cl and DMCl continued to rise during the entire treatment period. At the steady state, a correlation was found between Cl dosage expressed as mg kg body weight and the plasma concentration of Cl and DMCl. Factors such as tobacco and alcohol consumption seem to modify the Cl/DMCl ratio. A comparison of clinical response with plasma levels of Cl, DMCl and Cl + DMCl showed a significant negative linear correlation.
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  • 57
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    European journal of clinical pharmacology 22 (1982), S. 77-84 
    ISSN: 1432-1041
    Keywords: allopurinol ; oxipurinol ; benzbromarone ; hydrochlorothiazide ; pharmacokinetics ; bioavailability ; interaction
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary An high-pressure liquid chromatographic method was used to measure allopurinol and oxipurinol in plasma and urine in 6 healthy volunteers after a single intravenous or oral dose of allopurinol. The influence of coadministrated benzbromarone and hydrochlorothiazide on the pharmacokinetics of allopurinol and oxipurinol was also investigated. After intravenous injection of allopurinol 300 mg the plasma disappearance was biexponential, with a mean distribution half-life of 2.32±1.08 min $$(\bar x \pm SD)$$ and an elimination half-life of 47.8±10.6 min. The total clearance of allopurinol was 11.37±2.70 ml/min/kg, whereas its renal clearance was only 1.73±0.79 ml/min/kg. Oxipurinol disappeared monoexponentially from plasma ith a mean half-life of 12.2±2.6 h. Its renal clearance was 0.42±0.091 ml/min/kg. After oral administration of allopurinol 300 mg the peak plasma concentration of 2.1±0.6 µg/ml (1.5×10−5 M) was reached within 30 to 120 min. The peak level of oxipurinol of 5.8±1.5 µg/ml (3.8×10−5 M) was found within 2 to 5 h after intravenous and oral allopurinol. The bioavailability of oral allopurinol computed from plasma data was 90.4±8.7%. The total recovery from urine was 77% (allopurinol 8%, oxipurinol 69%) after oral and 88% after i.v. administration. It was concluded that about 10% of the oral dose was not absorbed and that 12% was eliminated by an unknown mechanism, presumably as riboside. The pharmacokinetics of allopurinol and oxipurinol were not significantly influenced by coadministration of benzbromarone or hydrochlorothiazide.
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  • 58
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    European journal of clinical pharmacology 22 (1982), S. 343-349 
    ISSN: 1432-1041
    Keywords: methadone ; opiate addicts ; pharmacokinetics ; single and multiple doses ; stable isotope technology ; methadone maintenance therapy ; deuterium technique
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Deuterated methadone (M-d30) and GC-MS were used to study the pharmacokinetics of methadone (M) during the induction stage of methadone maintenance treatment (MMT). A pulse dose of M-d3 was given on Days 1 and 25 of two dosage regimens, one with a continuous 30 mg dose (n=6), and the other with 30 mg for 10 days, followed by 60 mg as the maintenance dose (n=6). Plasma and urinary levels of M and M-d3 were measured throughout and plasma half-lives, oral bioavailabilities and volumes of distribution were calculated from the data of Days 1–2 and 24–26. The oral bioavailability of a methadone solution was found to be between 81 and 95%; elimination half-life in the β-phase varied between 19 and 58 h; the volume of distribution was 4.1±0.65 l/kg; and total body clearance of M was 54–195 ml/min and its renal clearance 3.4–34 ml/min. A consistent finding was a lower urinary pH and increased renal clearance during the first days of MMT as compared with after one month. In 4/12 of the patients dispositional tolerance was developed to methadone during the first month of treatment. The shorter elimination half-lives in those patients probably caused unacceptably high fluctuation in the body content of M during the 24 h dosage interval, and may have interfered therefore, with its therapeutic effectiveness
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  • 59
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    European journal of clinical pharmacology 22 (1982), S. 515-521 
    ISSN: 1432-1041
    Keywords: tienilic acid ; uricosuria ; pharmacokinetics ; pharmacodynamics ; uric acid ; diuretic ; plasma level assay
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary A simple and reliable HPLC method for the determination of tienilic acid ((TA) Selacryn®, Selcryn®, Diflurex®, Ticrynafen®) and its alcoholic metabolite in plasma and urine has been developed. In 8 healthy adult volunteers the plasma and urinary levels of tienilic acid and its alcoholic metabolite, and plasma and urinary levels of sodium, creatinine and uric acid were measured after oral administration of tienilic acid 250 mg. The pharmacokinetic parameters found differed only slightly from those reported in the literature, as there was faster absorption and a shorter half-life. TA is probably excreted by a saturable renal tubular transport mechanism. The pharmacodynamic effects of tienilic acid developed quickly, the uricosuric effect being very impressive and the natriuretic effect moderate. These effects disappeared in about 8 h. An inverse relationship was found between the starting plasma uric acid level in an individual and the maximal uric acid clearance — the higher the plasma uric acid level, the lower was the maximum effect. Plasma tienilic acid level and natriuretic effect were correlative within individuals and intra-individually (p〈0.05). Urinary tienilic acid level and natriuretic effect were correlated, too (p〈0.05 top〈0.001), but only intraindividually. No correlation between drug level and uricosuric effect was found.
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  • 60
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    European journal of clinical pharmacology 22 (1982), S. 535-539 
    ISSN: 1432-1041
    Keywords: noscapine ; pharmacokinetics ; absorption ; bioavailability ; intravenous application ; oral application ; ion exchange resin tablet
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Noscapine was administred to five healthy volunteers in a randomized crossover design, as an intravenous infusion of 66 mg, and as an oral 150 mg dose of either rapidly dissolving tablets or a tablet containing ion exchange resin-bound noscapine. After i.v. administration, the disposition of noscapine was bi-exponential with an elimination half-life of 2.6 h; the total plasma clearance was 22 ml/min/kg and the volume of distribution (Vdarea) was 4.7 l/kg. The absolute oral bioavailability was 30%, with a 3.6-fold interindividual variation. There was no pharmacokinetic evidence to support a prolonged action of the ion exchange resin tablet.
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  • 61
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    European journal of clinical pharmacology 22 (1982), S. 417-422 
    ISSN: 1432-1041
    Keywords: theophylline ; aminophylline ; obstructive airways disease ; short-term i.v. infusion ; log-normal distribution ; pharmacokinetics ; serum concentrations
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Serum theophylline concentrations after intravenous administration of a new short-term infusion (Euphyllin® Kurzzeitinfusion) were measured in 50 out-patients with chronic obstructive airways disease (COAD). An intravenous infusion of theophylline ethylenediamine 480 mg (corresponding to approximately 350 mg anhydrous theophylline) in 50 ml isotonic solution was given in 20 min. Blood samples were taken beforehand and 25 to 30 min and 1, 3 and 6 h after starting the infusion. 86% of the patients had a one-hour serum level in the therapeutic range of 8–20 mg/l, and 2 h later, this was true of 64% of the patients. The short-term infusion was well tolerated, even in cases with unknown high pre-infusion serum levels. Pertinent pharmacokinetic parameters were determined, such as total body clearance, apparent volume of distribution, and half-life of elimination. Geometric mean and 95%-confidence limits, derived from the log-normal distribution of these parameters, were: Cl=0.044 (0.018–0.109) l/h/kg ideal body weight, Vd=0.451 (0.258–0.789) l/kg ideal body weight, and t1/2(el)=7.1 (2.6–19.1) h.
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  • 62
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    European journal of clinical pharmacology 23 (1982), S. 249-252 
    ISSN: 1432-1041
    Keywords: mecillinam ; bacmecillinam ; pivmecillinam ; pharmacokinetics ; pro-drug ; healthy volunteers ; bioavailability
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of bacmecillinam and pivmecillinam were studied in healthy fasting volunteers given tablets in a cross-over, randomized order. The mean (±SD) peak levels of plasma mecillinam were 1.43±0.34, 2.73±0.43, and 4.62±1.41 mg/l after bacmecillinam 100, 200, and 400 mg and 2.38±0.65 mg/l after pivmecillinam 400 mg. The corresponding areas under plasma Vs time curves (AUC) were 2.21±0.19, 3.99±0.63, and 7.74±1.38 mg·h·l−1 for bacmecillinam and 5.35±0.93 mg·h·l−1 for pivmecillinam. The elimination half-lives were 0.8–1.1h for bacmecillinam and 0.7h for pivmecillinam. The 12 h urinary recovery of unchanged mecillinam after the 400 mg doses was 41% for bacmecillinam and 30% for pivmecillinam. The 400 mg dose of bacmecillinam gave a significantly higher plasma peak (p〈0.001), AUC (p〈0.001) and urinary recovery (p〈0.001) than did pivmecillinam 400 mg. The plasma peaks appeared earlier and the rate of absorption was higher after bacmecillinam than after pivmecillinam (p〈0.05). In conclusion, bacmecillinam had a better bioavailability than pivmecillinam in the tablet formulations studied. The AUC increased linearly with increasing doses of bacmecillinam.
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  • 63
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    European journal of clinical pharmacology 23 (1982), S. 267-270 
    ISSN: 1432-1041
    Keywords: terodiline ; human volunteers ; pharmacokinetics ; serum clearance ; bioavailability
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of terodiline HCl was studied in nine healthy volunteers given 12.5 mg i.v. and p.o. or 20 mg i.v. and 25 mg p.o. on two different occasions. The serum concentrations were measured by gas chromatography — mass spectrometry, using deuterated terodiline HCl as the internal standard. After i.v. administration the kinetics could be described by a two-compartment model with a mean distribution half life of 0.3 h and a mean elimination half life of 63 h. The serum clearance and apparent volume of distribution varied about 4-fold with mean values of 4.8 l/h and 417 l, respectively. After oral administration, the mean half life of absorption was 0.7 h and that of elimination 65 h. The absolute bioavailability varied between 64% and 105% with a mean of 92%. The long serum half life of terodiline should permit its once daily administration.
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  • 64
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    European journal of clinical pharmacology 23 (1982), S. 369-372 
    ISSN: 1432-1041
    Keywords: neuromuscular blockade ; pancuronium ; non-depolarizing neuromuscular blocking agent ; pharmacokinetics
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Pancuronium in bolus doses of 40 to 350 µg/kg was administered to surgical patients in order to evaluate the linearity of its pharmacokinetics. The profile of the plasma decay curve and of its urinary elimination were compared with reference to the administered dose. It was possible to superimpose the dose-normalized plasma decay-curves. The parameters of the two compartment-open model used to describe the pharmacokinetics of pancuronium were not influenced by the dose. The elimination half-life was 89±20 min and the plasma clearance was 1.84±0.38 ml/min/kg. The profiles of cumulative urinary excretion were also dose-independent. After 6 and 24 h, 57% and 69% of the administered dose, respectively, had been excreted in the urine. The results indicate that the pharmacokinetics of pancuronium is linear.
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  • 65
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    European journal of clinical pharmacology 23 (1982), S. 523-527 
    ISSN: 1432-1041
    Keywords: endralazine ; acetylator phenotype ; hydralazine ; pharmacokinetics ; plasma concentrations
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Five and 10 mg single oral doses of a new vasodilator antihypertensive, endralazine (E) were given on separate occasions to 17 normal male volunteers (8 slow, 7 heterozygous fast and 2 homozygous fast acetylators). The homozygous fast acetylators were excluded from statistical comparisons. Only small differences were observed in the pharmacokinetics of E between the phenotypes and there was no evidence of non-linearity at the 2 dose levels studied. Terminal half-lives ranged from 2.59 to 7.14 h with a mean of 4.30±1.08 h for the 5 mg dose and 4.25±1.09 h for the 10 mg dose. There was no significant difference in half-lives between slow and heterozygous fast acetylators. The mean area under the plasma level-time curve (AUC 0 ∞ ) was 18.2% lower (p〈0.05) in the heterozygous fast acetylators than in the slow acetylators following the 5 mg dose and 11.0% lower (p〉0.05) following the 10 mg dose. Extremely rapid absorption of the drug precluded accurate estimation of absorption rates. The AUC 0 ∞ of the acetylation metabolite (methyltriazoloendralazine) was small compared to that of E although higher in the heterozygous fast acetylators than in the slow acetylators (p〈0.01).
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  • 66
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    European journal of clinical pharmacology 22 (1982), S. 265-272 
    ISSN: 1432-1041
    Keywords: pharmacokinetics ; variation of absorption ratios ; bioavailability ; dissection of variation due to absorption and intermediate processes ; oral drug application
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    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Differences in the plasma concentrations of drugs after oral administration are caused by two main factors: variation in absorption ratios and in the distribution processes in the body. A new method for the dissection of both types of factors is discussed. The method uses a reference regression of the AUC-values to the corresponding values after intravenous infusion of graded doses. The reference regression is estimated from an appropriate trial. Deviation of the determined AUC-values from the regression curve afford an estimate of the residual variance due to varying distribution volumes or similar random biological effects. For the estimation of absorption ratios after oral administration the drug is given orally to another sample of subjects and their AUC-values are calculated. The deviation of these AUC values due to the above mentioned random effects are simulated using the residual variance of the reference regression, and are subtracted from the observed AUC-values. Then, the differences in the corresponding absorbed doses are transformed by inverting the reference regression. From these doses the empirical distribution function and statistical parameters (e.g. quantiles) are determined. The method has the advantage that no restrictive assumptions are required, such as first order processes, dose linearity, homogeneity of variance or normal distribution of absorption ratios. Its applicability to substances with qualitative differences in their pharmacokinetics is demonstrated by appropriate examples.
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    European journal of clinical pharmacology 22 (1982), S. 337-342 
    ISSN: 1432-1041
    Keywords: methadone ; pharmacokinetics ; urinary pH ; RBC level ; saliary level ; mass fragmentography
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The influence of urinary pH on the acute disposition of methadone in man was studied in five healthy volunteers. A cross-over experiment was performed in each subject. In the first experiment the subjects were treated with ammonium chloride (urinary pH ≈ 5.2) and in the other the urine was made alkaline (pH ≈ 7.8) by treatment with sodium hydrogen carbonate. d, 1-Methadone-HCl 10 mg (M) was administered intramuscularly on each occasion and blood, saliva and urine levels of M were determined by mass fragmentography. Plasma half-lives, volumes of distribution and body clearances of M were calculated in both experiments. The plasma half-lives in the β-phase were 19.5±3.6 h (acidic urine) and 42.1±8.8 h (alkaline urine), respectively (p〈0.001). The volumes of distribution were increased when the pretreatment was changed from ammonium chloride to sodium bicarbonate, namely from 3.51±0.41 l/kg to 5.24±0.83 l/kg (p〈0.01). The body clearance decreased from 134±21 ml/min (acidic) to 91.9±9.1 ml/min (alkaline urine) (p〈0.01). The ration Mplasma/MRBC was about 2.3 and the elimination of M from RBCs was in good agreement with the plasma kinetics of M under both experimental conditions. The salivary levels of M did not reflect the plasma kinetics and considerable variation was seen in the ratio Msaliva/Mplasma (0.26–2.98). Thus, the present experiments demonstrate that pretreatment either with ammonium chloride or bicarbonate had profound effects on both the distribution and elimination kinetics of methadone.
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    European journal of clinical pharmacology 23 (1982), S. 435-440 
    ISSN: 1432-1041
    Keywords: erythromycin ; haemodialysis ; dosage adjustment ; pharmacokinetics ; protein-binding
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Erythromycin kinetics were studied in 17 patients with end stage renal failure treated with maintenance haemodialysis and 9 normal volunteers to discover if dialysis patients needed a modified dose. The elimination half life in dialysis patients (on dialysis days) was similar to that reported in normal subjects. Only small amounts of drug appeared in the dialysate, no patient loosing more than 9 mg in one dialysis. Both patients and volunteers had similar plasma concentrations 8 h after the end of a 5-day course. Protein-binding did not change significantly during dialysis and was similar to that reported in normal subjects. We conclude that dialysis patients requiring 1.5 g of erythromycin stearate daily or less can be given normal doses.
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  • 69
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    Journal of nondestructive evaluation 3 (1982), S. 55-63 
    ISSN: 1573-4862
    Keywords: ultrasonics ; Rayleigh waves ; subsurface defects ; NDE
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    Topics: Electrical Engineering, Measurement and Control Technology , Mathematics
    Notes: Abstract An ultrasonic inspection method is used to obtain the circumference of a subsurface hole and the depth of the hole below the surface. A pitch-catch Rayleigh wave transducer set-up was used to launch a Rayleigh surface wave at the flaw and to capture and record the scattered waves. The frequency spectrum of the scattered waves can be used to obtain the depth of the hole. The ligament of material between the hole and the surface is sent into resonance, and this feature can be extracted from the scattered waves' frequency spectrum. The frequency is a function of the ligament length; thus the hole depth can be obtained. The circumference of the hole is found from a time of flight measurement. A Rayleigh wave is formed that travels around the hole's surface. The length of time required for the wave to travel around the hole is a measure of the circumference.
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  • 70
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    Journal of nondestructive evaluation 3 (1982), S. 65-76 
    ISSN: 1573-4862
    Keywords: crack measurement ; ac field technique ; arbitrary skin depth ; NDE
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    Topics: Electrical Engineering, Measurement and Control Technology , Mathematics
    Notes: Abstract A general solution is given to describe the ac field around surface-breaking cracks for arbitrary values of the ratio of skin depth δ to crack depthd. This solution allows accurate interpretation of crack depth from voltage readings taken by a Crack Microgauge instrument in cases where δ andd are comparable. It is shown to agree with asymptotic formulae obtained for the cases where δ/d is very small and very large. Provided that the probe length Δ is large compared with δ, the calculations show that a very good approximation to the crack depth may be obtained, irrespective of the ratio δ/d, by using the thin-skin asymptotic formula $$d = \frac{1}{2}\Delta (V_2 - V_1 )/V_1 $$ whereV 1 andV 2 are probe voltages registered at positions just off and across the crack, respectively. The problem is solved for a crack of infinite aspect ratio which has no opening, but it can be applied with confidence at the centerline of cracks of fairly large aspect ratio.
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  • 71
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    Journal of nondestructive evaluation 3 (1982), S. 99-109 
    ISSN: 1573-4862
    Keywords: thermography ; infrared scanning ; calibration ; inverse problems ; cavity detection ; NDE
    Source: Springer Online Journal Archives 1860-2000
    Topics: Electrical Engineering, Measurement and Control Technology , Mathematics
    Notes: Abstract An approach for treating nondestructive testing as the solution of inverse problems in mathematical physics has been used for the detection of cavities. The approach is developed based on the use of an additional boundary condition of scanned temperature on the surface to solve for the cavity geometry. For the present study, the condition at the cavity side is taken to be that of a specified temperature, and the experiment is carried out to meet this condition. Two specimens are tested in this paper, a plane slab and a rectangular prism. In both bodies the cavity is rectangular in shape. For the testing of the plane slab, the method is able to detect the cavity wall with high accuracy, whereas the cavity depth error is larger (6%). The detection of the cavity position in the rectangular prism has an error ranging from −9.7 to 7.7%. Errors in the experiment are attributed to the uncertainties in the measurements of temperature and the Biot number. The former is read off from the analog data output of the infrared scanner. The latter is not measured separately, but is computed from the scanned data and thus becomes a portion of the total nondestructive testing output. A final note is also made in this paper to relate how the presented method can be used in actual practice.
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    Journal of nondestructive evaluation 3 (1982), S. 175-182 
    ISSN: 1573-4862
    Keywords: ultrasonic wave scattering ; inclusions ; reciprocity ; NDE
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    Topics: Electrical Engineering, Measurement and Control Technology , Mathematics
    Notes: Abstract This paper, as part of a series on elastic wave scattering, presents results of measurements and calculations on scattering of ultrasonic waves by a solid spherical inclusion (tungsten carbide) embedded in titanium alloy by the diffusion bonding process. Both direct scattering and mode-converted scattering angular distributions are reported for shear and compressional incident waves. The consequences upon the signals when transmitter and receiver were interchanged are explored in a reciprocity rule.
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  • 73
    ISSN: 1573-4927
    Keywords: aldehyde oxidase ; pyridoxal oxidase ; tissue specificity ; Drosophila
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    Topics: Biology , Chemistry and Pharmacology
    Notes: Abstract The substrate specificities of aldehyde and pyridoxal oxidases in Drosophila melanogaster have been determined with a variety of aliphatic and aromatic aldehydes. This analysis has led to the discovery that 2,4,5-trimethoxy-benzaldehyde is a specific substrate for pyridoxal oxidase, as based on the histochemical distribution of oxidase activity, the absence of enzymatic activity in the lpo 1strains, and the dosage dependence on the number of lpo +genes present. The tissue-specific localization of aldehyde oxidase (AO) and pyridoxal oxidase (PO) in the larval and adult structures showed that AO was present in all the major internal organs of the larvae and adults, including brain, imaginal discs, Malpighian tubules, digestive system, and reproductive structures. Pyridoxal oxidase is present in many of the same structures which possess AO, but is missing from the cardia, crop, imaginal discs, ovarian follicle cells, paragonia, pericardial cells, and wreath cells. The only structure which possesses PO but lacks AO is the larval salivary gland. These histochemical differences in AO and PO distribution were also confirmed by enzymatic analysis of the activities present in homogenates of ovaries, paragonia, and salivary glands. The general pattern of enzyme expression appears to be established during embryogenesis and maintained throughout the life of the individual.
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    Biochemical genetics 20 (1982), S. 461-474 
    ISSN: 1573-4927
    Keywords: Drosophila ; allozymes ; α-Gpdh ; selection ; genetic background
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology
    Notes: Abstract Three sets of experiments have been conducted in order to evaluate the role of natural selection at the α-Gpdh locus in Drosophila melanogaster. (1) The evolution of the F-allele frequency has been followed for many generations in 13 experimental populations having different genetic backgrounds. (2) Egg-to-adult viability has been measured in synthetic populations derived from one locality (Brouilly) and the results have been compared with those of a previous experiment involving a different local population (Tostes). (3) The effects of sodium octanoate on egg-to-adult viability have been measured on the genotypes FF, FS, SF, and SS. The results demonstrate that selection operates on a small block of genes which includes the α-Gpdh locus.
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  • 75
    ISSN: 1573-4927
    Keywords: esterase ; duplication ; gene expression ; Drosophila
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    Topics: Biology , Chemistry and Pharmacology
    Notes: Abstract An esterase duplication is described in the sibling species pair Drosophila mojavensis and Drosophila arizonensis. We present evidence for two separate structural loci mapping at a distance of less than 0.16 recombination units from each other. Alleles at the two loci have the same substrate specificities and form small amounts of interlocus heterodimers. One locus (Est-5) is functioning throughout the insect's life cycle and appears at high concentrations in the hemolymph and the fat body. Its duplicate (Est-4) functions only during the late larval stage and is concentrated mainly in the carcass. No null alleles at either locus were observed in population surveys. An examination of 12 other species from the repleta group, to which D. mojavensis and D. arizonesis belong, suggests that Est-5 is universally present, but the activity levels of Est-4 vary among species and may be totally absent in some species. Variation in the level of Est-4 activity does not closely follow the phylogenetic relationship.
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  • 76
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    Biochemical genetics 20 (1982), S. 179-198 
    ISSN: 1573-4927
    Keywords: acetylcholinesterase ; Drosophila ; malathion ; insecticide resistance
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    Topics: Biology , Chemistry and Pharmacology
    Notes: Abstract The relationship between the 50% survival time for flies feeding on a malathion-containing medium and the activity of acetylcholinesterase (AChE) was determined for 15 isofemale lines of Drosophila melanogaster. A significant correlation was found (r=0.28, P〈0.05), with more resistant lines tending to have a lower level of AChE activity. An association between AChE and malathion resistance was also observed in a selection experiment. The AChE activity decreased in two of two populations selected for malathion resistance. AChE from these populations was altered in kinetic parameters (measured in crude head extracts) and electrophoretic mobility. Although the “resistant” AChE had a lower activity (V m) on either a per milligram protein or a per individual basis, its apparent K m for acetylthiocholine was lower than that of “susceptible” AChE. Recombination mapping of both low activity and fast electrophoretic mobility localized these traits to the region of the structural locus (Ace) on the third chromosome. The AChE activity of flies heterozygous for a variety of Ace lesions (kindly provided by Dr. W. M. Gelbart) was consistent with this location. The changes in AChE were suggested to have been caused by selection of alleles at the Ace locus.
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    Journal of nondestructive evaluation 3 (1982), S. 19-24 
    ISSN: 1573-4862
    Keywords: ac potential difference ; eddy current ; fatigue crack measurement ; skin effect equation ; large skin depth ; NDE
    Source: Springer Online Journal Archives 1860-2000
    Topics: Electrical Engineering, Measurement and Control Technology , Mathematics
    Notes: Abstract This paper considers the solution of the skin-effect or Helmholtz equation, ∇2ψ=k 2ψ, for the two-dimensional flow of a uniform alternating current perturbed by a plane crack of uniform depth. Herek is the ratio of crack depthd to skin depth δ. When the skin depth is large compared with the crack depth andk f 0, the quasi-static approach to this problem ignores the terms on the right-hand side and constructs solutions from Laplace's equation which are essentially dc solutions and are correct to orderk. In this paper we consider behavior near the limit when the skin depth is large and give solutions which are correct to orderk 2. In an example we relate the results to the interpretation of readings from an ac potential difference instrument applied to the measurement of surface-breaking cracks.
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    Journal of nondestructive evaluation 3 (1982), S. 93-98 
    ISSN: 1573-4862
    Keywords: bounded ultrasonic beam reflectivity ; Rayleigh angle ; beam profile ; surface defects ; nonspecular reflection ; NDE
    Source: Springer Online Journal Archives 1860-2000
    Topics: Electrical Engineering, Measurement and Control Technology , Mathematics
    Notes: Abstract The relationships between characteristics of elastic defects and nonspecular features of bounded ultrasonic beams reflected at the Rayleigh angle from a liquid-solid interface are investigated. The results can serve as a theoretical basis for interpretation of Rayleigh angle nonspecularly reflected beam profiles as characterization of localized surface elastic defects.
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    Journal of nondestructive evaluation 3 (1982), S. 125-136 
    ISSN: 1573-4862
    Keywords: magnetic particle inspection ; magnetic leakage fields ; finite difference method ; NDE
    Source: Springer Online Journal Archives 1860-2000
    Topics: Electrical Engineering, Measurement and Control Technology , Mathematics
    Notes: Abstract Experimental measurements of leakage fields from cylindrical defects were obtained in a geometry which permitted simultaneous measurement of the magnetic induction of the material. The results obtained are compared with calculations using a nonlinear finite difference method. Both the experiments and the calculations indicate that the magnitude of the leakage field continues to grow nearly in proportion with the applied field well into the saturation region of the magnetic material. The implications for magnetic particle inspection are discussed.
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  • 80
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    Journal of nondestructive evaluation 3 (1982), S. 45-53 
    ISSN: 1573-4862
    Keywords: Born approximation ; ultrasonic scattering ; NDE ; time domain
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    Topics: Electrical Engineering, Measurement and Control Technology , Mathematics
    Notes: Abstract The time domain Born approximation for ultrasonic scattering from volume flaws in an elastic medium is described. Results are given both for the direct and the inverse problem. The time domain picture leads to simple intuitive formulas, which we illustrate by means of several simple examples. Particular emphasis is given to the front surface echo and its use in reconstructing the properties of the flaw.
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    Journal of nondestructive evaluation 3 (1982), S. 183-188 
    ISSN: 1573-4862
    Keywords: Ultrasonics ; Born inversion ; NDE
    Source: Springer Online Journal Archives 1860-2000
    Topics: Electrical Engineering, Measurement and Control Technology , Mathematics
    Notes: Abstract Quantitative reconstruction of volumetric flaws near a surface of an elastic solid has been carried out experimentally by analyzing the scattered ultrasonic waves. The inverse Born approximation (developed for flaws in bulk materials) was tested for the first time in the determination of the size, shape, and orientation of near-surface flaws. We have studied spherical solid inclusions at various depths below the surface. In addition we examined an approximately 2:1 prolate spheroidal inclusion which was located one major axis below the surface. The determination of the flaw's size, shape, and orientation in terms of an equivalent ellipsoid is realized by performing nonlinear least-squares iteration of the one-dimensional Born inversion results obtained at various scattering directions within a finite aperture. The reconstruction is in good agreement with the actual parameters of the flaw.
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  • 82
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    Journal of nondestructive evaluation 3 (1982), S. 9-17 
    ISSN: 1573-4862
    Keywords: ac potential difference ; probe characterization ; induction effect ; slots ; fatigue crack ; NDE
    Source: Springer Online Journal Archives 1860-2000
    Topics: Electrical Engineering, Measurement and Control Technology , Mathematics
    Notes: Abstract In the ac field method of crack depth measurement by the Crack Microgauge, the area of the loop formed in the probe gives rise to an induced voltage, which can introduce errors into the depth measurement. In this paper, a method for measuring the probe area is given, and the quality of the probe is thereby characterized. The underlying theory was given previously, and it is applied here to the probe characterization problem. The probe area is determined by two voltage measurements taken on an artificial rectangular flaw machined in an arbitrary metal. By measurements on several such specimens with the same probe, it is confirmed that the area so obtained is a characteristic of the probe and is independent of the specimen material. Thereafter, measurements on various rectangular flaws with probes of different characteristic area were taken, and very good agreement between predicted and real depths was achieved. Both theory and experiments show that probe characterization is of particular importance when this method is used to measure surface crack depths in metals of low permeability such as aluminum.
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    Journal of nondestructive evaluation 3 (1982), S. 37-43 
    ISSN: 1573-4862
    Keywords: eddy current ; impedance ; lift-off ; flaw ; NDE
    Source: Springer Online Journal Archives 1860-2000
    Topics: Electrical Engineering, Measurement and Control Technology , Mathematics
    Notes: Abstract The problem of detection and characterization of a flaw in a conducting half-space using an eddy-current coil oriented parallel to the interface is examined. An expression is derived for a first order approximation for the change in complex impedance due to a flaw located within the conducting medium. The overall impedance is a function of the radius and lift-off distance of the test coil and the conductivity of the material. An analytical expression is derived for the change in impedance as a function of the electric fields at the position of the flaw. It is found to be an integral over the volume of the flaw of the electric fields found with and without the flaw being present. The limiting case of a degenerate point flaw may be examined in greater detail by allowing the field in the presence of the flaw to be approximated by the unperturbed field. For flaws small enough that the field does not vary much over its volume, the field may be even further approximated by using just the value of the field at the position of the centroid of the flaw. Plots are shown to illustrate the behavior of the change in impedance as a function of the radial range of the flaw and the depth of the flaw centroid, using previously derived expressions for the fields for the unflawed case.
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    Journal of nondestructive evaluation 3 (1982), S. 85-91 
    ISSN: 1573-4862
    Keywords: displacement-field ; acoustic radiation ; wave propagation ; absolute velocity ; EMAT ; mode selective ; nonresonant frequency response ; NDE
    Source: Springer Online Journal Archives 1860-2000
    Topics: Electrical Engineering, Measurement and Control Technology , Mathematics
    Notes: Abstract A new electromagnetic acoustic transducer (EMAT) is developed that measures velocities and absolute surface displacements in-plane and plane-normal to the direction of wave propagation. This transducer is flexible in shape and design to conform with irregular surfaces and has unique characteristics of nonresonant frequency response. Tests show that the sensitivity of this EMAT can be increased by increasing the applied magnetic field. Because this transducer is mode selective and nonresonent, its response can be related uniquely to the wave motion. This property is highly desirable for research purposes, though generally not wanted in field monitoring situations.
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    Journal of nondestructive evaluation 3 (1982), S. 221-227 
    ISSN: 1573-4862
    Keywords: Radiography ; point-spread function ; corner location ; edge location ; unsharpness ; NDE
    Source: Springer Online Journal Archives 1860-2000
    Topics: Electrical Engineering, Measurement and Control Technology , Mathematics
    Notes: Abstract Two-dimensional imaging properties of locally isotropic and isoplanatic point spread functions are described in a general radiographic context. In particular, the radiographic response to a two-dimensional wedge-shaped object is shown to possess several properties which enable the identification of the wedge corner on the image, thereby alleviating the need for image enhancement techniques. Extensions to the location of flat-edged boundaries are also discussed. The potential dimensioning application of this analysis lies in the precise and objective location of points of interest on radiographs of more complex two-dimensional objects.
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    Biochemical genetics 20 (1982), S. 407-424 
    ISSN: 1573-4927
    Keywords: dipeptidases ; Drosophila ; variation
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    Topics: Biology , Chemistry and Pharmacology
    Notes: Abstract Three dipeptidases in Drosophila melanogaster are under independent genetic control and their structural genes have been localized, Dip-A to 2R and Dip-B and Dip-C to 3R (Voelker and Langley, 1978; Ohnishi and Voelker, 1981). These enzymes were characterized with respect to their substrate specificities, genetic variability (electrophoretic mobility and quantitative activity level), ontogeny (activity and isozyme pattern), and tissue localization. The dipeptide substrate specificities of DIP-A and DIP-B overlap each other considerably, but do not overlap with DIP-C. In natural populations, DIP-B and DIP-C are essentially monomorphic electrophoretically whereas DIP-A is polymorphic for three allozymes. Both DIP-A and DIP-B show quantitative genetic variation of activity level within an allozyme class. All three enzymes are expressed at all stages in the life cycle, but DIP-A and DIP-B activities vary considerably according to developmental stage and sex of adult. The tissue localizations of DIP-A and DIP-B activities show similar patterns and a nearly ubiquitous occurrence of both enzymes, but with particularly high values in larval and adult midguts and in the adult female reproductive system. These results suggest a general metabolic role for the enzymes, such as regulation of the concentrated pools of amino acids and oligopeptides found in Drosophila tissues.
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    Journal of nondestructive evaluation 3 (1982), S. 229-239 
    ISSN: 1573-4862
    Keywords: Crack-opening displacement ; crack closure ; ultrasonics ; Kirchoff approximation ; NDE
    Source: Springer Online Journal Archives 1860-2000
    Topics: Electrical Engineering, Measurement and Control Technology , Mathematics
    Notes: Abstract The interaction between rough crack faces is modeled by nonlinear relations between the crack-face tractions and the crack-opening displacements. These relations account for crack closure and for the related resistance to crack-face sliding. The relations are used to investigate reflection and transmission of an incident pulse by an infinite flaw plane. The problem statement is reduced to a set of inhomogeneous nonlinear ordinary differential equations for the displacement discontinuities, [u] and [v], across the flaw plane. These equations have been solved numerically. The reflection and transmission of an incident pulse by a crack with interacting crack faces. Both incident longitudinal and transverse waves have been considered. The loss of specular reflection as compared to a perfect (traction-free) crack is exhibited by specific examples.
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    Journal of nondestructive evaluation 3 (1982), S. 1-8 
    ISSN: 1573-4862
    Keywords: acoustoelasticity ; transverse isotropy ; polycrystalline aggregate ; cubic crystal ; third-order elastic constants ; NDE
    Source: Springer Online Journal Archives 1860-2000
    Topics: Electrical Engineering, Measurement and Control Technology , Mathematics
    Notes: Abstract Acoustoelasticity is an ultrasonic technique which has been used for the determination of active and residual stresses in common structural materials. This paper examines the effect of texture on the acoustoelastic response in polycrystalline bodies. In particular materials which are transversely isotropic aggregates of cubic crystals are studied. The second- and third-order elastic constants of the polycrystal are derived from the elastic properties of the constituent crystals, and the crystalline orientation relative to the body's symmetry axis. The acoustoelastic relations between velocity and deformation are then presented for the aggregate. Finally, evaluation of the acoustoelastic response for several ideal textures using data for aluminum single crystals shows that the response is highly dependent on the texture.
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    Journal of nondestructive evaluation 3 (1982), S. 111-113 
    ISSN: 1573-4862
    Keywords: photoacoustic microscopy ; delamination ; layered structure ; NDE
    Source: Springer Online Journal Archives 1860-2000
    Topics: Electrical Engineering, Measurement and Control Technology , Mathematics
    Notes: Abstract An adhesive layer, by which a piezoceramic foil is attached to an aluminum membrane for telephone application, is examined in a nondestructive way by thermal waves. The basic principles of the method are outlined, and its detecting power is demonstrated by evaluation of a well-defined delamination.
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    Journal of nondestructive evaluation 3 (1982), S. 147-154 
    ISSN: 1573-4862
    Keywords: finite element modeling ; eddy current ; absolute probe ; steam generator tubing ; NDE
    Source: Springer Online Journal Archives 1860-2000
    Topics: Electrical Engineering, Measurement and Control Technology , Mathematics
    Notes: Abstract Finite element analysis techniques are applied to the problem of predicting signals from an absolute eddy current probe in the tube sheet region of a PWR steam generator for the purpose of optimizing the probe coil geometry and determining the feasibility of using such a probe to characterize the condition of the tube and tube sheet crevice.
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  • 91
    ISSN: 1573-4862
    Keywords: Acoustic harmonic generation ; critical angle acoustics ; fatigue crack detection ; alloy microstructure ; load amplitude ; NDE
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    Topics: Electrical Engineering, Measurement and Control Technology , Mathematics
    Notes: Abstract Alloy grain size is known to influence both the propagation path and the closure stress of surface fatigue cracks in many alloys. The general trend is for the path to be more tortuous and the closure stress to be larger, the larger the grain size. By use of Ti Al-4V and Al 7075-T6, the effects of grain size on the nondestructive detection of surface cracks which might arise from closure stress and path irregularity variables were evaluated. Titanium specimens were inspected using an acoustic harmonic generation technique, and it was discovered that the major source of harmonic signals was grain sized crystallographic cracks. Harmonic signals were larger during fatigue in an 8-µm compared to a 4-µm grain sized alloy, as there were more grain sized cracks in the large grain material. Crack closure was found to be extremely important in determining the reflected acoustic amplitude obtained in inspecting small (100–1000 µm) cracks in Al 7075-T6 using a critical angle technique. Average received amplitudes were an order of magnitude smaller for cracks at zero load than for those opened by a tensile stress. The scatter in the reflected amplitude was also large, apparently as the result of variations in the degree of the closure from crack to crack. For the 7075 material, the important effect of larger grain size was to increase the irregularity of the crack path, making the small cracks more visible acoustically at azimuthal angles not normal to the crack plane.
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    Journal of nondestructive evaluation 3 (1982), S. 137-145 
    ISSN: 1573-4862
    Keywords: jadeite authentication ; 14 MeV neutrons ; jades ; NDE
    Source: Springer Online Journal Archives 1860-2000
    Topics: Electrical Engineering, Measurement and Control Technology , Mathematics
    Notes: Abstract Fourteen MeV neutron activation of jades was used to test the authenticity of jades: to ascertain whether they are genuine jadeite and whether their greenish colour is genuine, both of which are important criteria for the high market value of jadeite. For given activation and measurement conditions of the jades, the gamma-ray spectrum was observed to change as a function of the type of the jades; the counting ratio of the photopeaks from the two most prominent constituent elements varies greatly as a function of the type of the jades. The ratio of counts for the Compton edges of the 1.779 MeV gamma-ray of28Al, from28Si(n,p)28Al reaction, and the 1.434 MeV gamma-ray of52V, from52Cr(n,p)52V reaction, varied as a function of the type of the jades and also as a function of the color. These results can be applied for a fast and nondestructive evaluation of jades.
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  • 93
    ISSN: 1573-4927
    Keywords: alcohol dehydrogenase ; Drosophila ; selection ; ethanol ; temperature
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology
    Notes: Abstract Drosophila melanogaster larvae were subjected to 10 generations of selection on 6% ethanol at 17, 25, and 30°C. For each temperature there was a significant (P〈0.01) increase in the frequency of the Adh isoallele. Controls with no ethanol showed no change in the frequency of the Adh F isoallele. Larvae subjected to stronger selection on 8% ethanol confirmed the results. When adults of various ages were subjected to 16 and 32°C, the ADHF isoenzyme retained its twofold advantage in activity over ADHS regardless of the temperature. The same result was obtained with larvae at 16 and 35°C. Although some effect of temperature was demonstrated, it was concluded that the effect was not strong enough for temperature to be a selective factor under the conditions studied. However, ethanol is a strong selective factor for laboratory populations.
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  • 94
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    Theoretical and applied genetics 63 (1982), S. 193-199 
    ISSN: 1432-2242
    Keywords: Drosophila ; Polytene nuclei ; Underreplication ; Polytenization ; Cytophotometry ; Heterochromatin
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary Recent cytophotometric DNA determinations and results of labeling experiments are compared with results of biochemical experiments concerning larval polytene salivary gland nuclei of Drosophila melanogaster. Recent publications (Dennhöfer 1981; 1982 a, b) demonstrate that methodological errors both in hydrolysis of the DNA before Feulgen reaction and in interpretation of the cytophotometric values give raise to the hypothesis of heterochromatic underreplication during polytenization. It is concluded also that methodological difficulties cause the absence of polytene SAT-DNA in biochemical centrifugation experiments since, because of different solubilities of eu- and heterochromatic DNA, the latter is not resolved in DNA isolation procedures from polytene nuclei.
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  • 95
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    Bulletin of experimental biology and medicine 94 (1982), S. 1069-1071 
    ISSN: 1573-8221
    Keywords: pharmacokinetics ; alcohol ; alcohol abstinence
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
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  • 96
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    Bulletin of experimental biology and medicine 94 (1982), S. 1373-1375 
    ISSN: 1573-8221
    Keywords: pharmacokinetics ; phenazepam ; 3-hydroxyphenazepam ; cats ; blood ; metabolic model
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
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  • 97
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    Bulletin of experimental biology and medicine 94 (1982), S. 1689-1692 
    ISSN: 1573-8221
    Keywords: ethanol preference ; endogenous ethanol ; pharmacokinetics ; estrous cysle
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
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  • 98
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    Journal of pharmacokinetics and pharmacodynamics 10 (1982), S. 465-494 
    ISSN: 1573-8744
    Keywords: disopyramide ; pharmacokinetics ; bioavailability ; metabolite ; half-life ; protein binding ; disease states ; drug-drug interaction
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Current information on the pharmacokinetics of disopyramide is reviewed with emphasis on the implications for antiarrhythmic therapy. The absolute bioavailability, the disposition half-life, the plasma clearance, and the renal clearance for normal subjects and patients are discussed. Drug-drug interactions are discussed, and a new flexible intravenous dosing schedule is proposed.
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  • 99
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    Journal of pharmacokinetics and pharmacodynamics 10 (1982), S. 335-348 
    ISSN: 1573-8744
    Keywords: pharmacokinetics ; bioavailability ; growth ; literature growth ; logistic function
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The literature growth in pharmacokinetics and bioavailability between the years 1964 and 1980 is analyzed. During much of this period, the literature doubled approximately every 1.6 years. However, during the period 1978–1980, little or no growth was observed. During the period 1950–1967, the total chemical literature increased exponentially with a half-life of 8.28 years; between 1968 and 1980, the half-life was 12.4 years. Thus, the pharmacokinetic literature increased at a much more rapid pace than did the total chemical literature in general. The subject of growth is considered in a general context, particularly as influenced by psychological, sociological, political, and economic factors. It is concluded that while mathematical functions may adequately describe past literature trends, they have little if any utility in predicting future trends in specific research areas such as pharmacokinetics.
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  • 100
    ISSN: 1573-8744
    Keywords: chloramphenicol-3-monosuccinate ; chloramphenicol-1-monosuccinate ; chloramphenicol ; bioavailability ; pharmacokinetics ; intravenous administration ; adult patients
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The pharmacokinetics of chloramphenicol (CAP) and total chloramphenicol succinate (CAPS) were studied in eight hospitalized adult patients with normal renal and hepatic function receiving intravenous chloramphenicol sodium succinate therapy. The steady-state peak concentrations of CAP (8.4–26.0 μg/ml) occurred at an average of 18.0 min (range 5.4–40.2) after cessation of the chloramphenicol sodium succinate infusion. Unhydrolyzed CAPS prodrug, representing 26.0±7.0% of the dose, was recovered unchanged in the urine indicating that the bioavailability of CAP from a dose of intravenous chloramphenicol succinate is not complete. A pharmacokinetic model was developed for simultaneous fitting of CAP and CAPS plasma concentration data. Pharmacokinetic parameters determined by simultaneous fitting were: V, 0.81±0.18 liters/kg; t1/2, 3.20 ±1.02 hr; CLB, 3.21±1.27 ml/min/kg for chloramphenicol; and V, 0.38±0.13 liters/kg; t1/2, 0.57±0.12hr; CLB, 7.72±1.87 ml/min/kg for total chloramphenicol succinate.
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