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  • Articles  (177)
  • pharmacokinetics  (96)
  • wheat  (55)
  • stability
  • Springer  (177)
  • 1990-1994  (177)
  • 1991  (177)
  • 1
    Electronic Resource
    Electronic Resource
    Stability properties of proliferatively coupled cell replication models (1991)
    Springer
    Acta biotheoretica 39 (1991), S. 1-14 
    Details
    ISSN: 1572-8358
    Keywords: Hematological diseases ; first order partial differential equations ; stability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract To address the possibility that proliferative disorders may originate from interactions between multiple populations of proliferating and maturing cells, we formulate a model for this process as a set of coupled nonlinear first order partial differential equations. Using recent results for the asymptotic behaviour of the solutions to this model, we demonstrate that there exists a region of coupling coefficients, maturation rates, and proliferation rates that will guarantee the stable coexistence of coupled cellular populations. The analysis shows that increases in the coupling between populations may ultimately lead to a loss of stability. Furthermore, the analysis indicates that increases (decreases) in the maturation and/or proliferation rates above (below) critical levels will lead either to instability in the populations or the destruction of one population and the persistence of the other.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00046404
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  • 2
    Electronic Resource
    Electronic Resource
    Influence of washing and of heat-treatment conditions on the thermal stability of VPI-5 (1991)
    Springer
    Catalysis letters 10 (1991), S. 225-232 
    Details
    ISSN: 1572-879X
    Keywords: VPI-5 ; stability ; molecular sieve ; post-synthesis treatments
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Thorough washing of a VPI-5 synthesized with n-dipropylamine as template improves greatly its thermal stability while no major change is observed in the template content. A detailed study of the influence of the pretreatment conditions shows that in order to obtain a high thermal stability (up to at least 960 °C) two parameters are of importance. The removal of both the template and the adsorbed water requires either a low heating rate at atmospheric pressure or a low pressure (less than 3 Torr) when the heating rate is 300 ° per hour.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00772075
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  • 3
    Electronic Resource
    Electronic Resource
    Multivariate exploratory data analysis in chemical industry (1991)
    Springer
    Microchimica acta 104 (1991), S. 467-482 
    Details
    ISSN: 1436-5073
    Keywords: prediction ; stability ; multivariate methods ; graphical analysis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Sizeable data bases are now being routinely generated in a variety of contexts in chemical industry. Statistical investigations of such data bases are aimed both at initially uncovering structure and eventually proposing models, in particular for predicting product quality by the mix or characteristics of the chemical compounds. “Online Multivariate Exploratory Graphical Analysis” (OMEGA) stands for a structured exploratory study of the relationships in a multivariate data set, where, rather than testing for one specific property, as many clues as possible for interesting structures are searched for by different dimension reductions and succeeding interactive graphical analyses. The stability of the projections obtained by the different dimension reduction methods is assessed by simulation producing graphical displays particularly supporting the identification of influential points. The variation of the predictions obtained by the different dimension reduction methods is assessed by cross-validation delivering misclassification rates or cross-validated R2 values. The interpretation of the new coordinates corresponding to dimension reduction is supported by loading simplifications and graphical displays for judging its adequacy. The OMEGA strategy has been found to be an effective tool for routine searching for structure.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01245532
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  • 4
    Electronic Resource
    Electronic Resource
    Nonabelian K-theory: The nilpotent class of K 1 and general stability (1991)
    Springer
    K-Theory 4 (1991), S. 363-397 
    Details
    ISSN: 1573-0514
    Keywords: Nonabelian K 1 ; noncommutative homotopy ; general linear group ; superspecial linear groups ; descending central series ; stability ; relative normal subgroups ; nilpotent sandwich classifications ; quasi-finite algebras
    Source: Springer Online Journal Archives 1860-2000
    Topics: Mathematics
    Notes: Abstract A functorial filtration GL n =S−1L n $$ \supseteq$$ S0L n $$ \supseteq$$ ⋯ $$ \supseteq$$ S i L n $$ \supseteq$$ ⋯ $$ \supseteq$$ E n of the general linear group GL n, n ⩾ 3, is defined and it is shown for any algebra A, which is a direct limit of module finite algebras, that S−1 L n (A)/S0L n (A) is abelian, that S0L n (A) $$ \supseteq$$ S1L n (A) $$ \supseteq$$ ⋯ is a descending central series, and that S i L n (A) = E n(A) whenever i ⩾ the Bass-Serre dimension of A. In particular, the K-functors k 1 S i L n =S i L n /E n are nilpotent for all i ⩾ 0 over algebras of finite Bass-Serre dimension. Furthermore, without dimension assumptions, the canonical homomorphism S i L n (A)/S i+1 L n (A)→S i L n+ 1(A)/S i+1 L n + 1 (A) is injective whenever n ⩾ i + 3, so that one has stability results without stability conditions, and if A is commutative then S0L n (A) agrees with the special linear group SL n (A), so that the functor S0L n generalizes the functor SL n to noncommutative rings. Applying the above to subgroups H of GL n (A), which are normalized by E n(A), one obtains that each is contained in a sandwich GL′ n (A, ρ) $$ \supseteq$$ H $$ \supseteq$$ E n(A, ρ) for a unique two-sided ideal ρ of A and there is a descending S0L n (A)-central series GL′ n (A, ρ) $$ \supseteq$$ S0L n (A, ρ) $$ \supseteq$$ S1L n (A, ρ) $$ \supseteq$$ ⋯ $$ \supseteq$$ S i L n (A, ρ) $$ \supseteq$$ ⋯ $$ \supseteq$$ E n(A, ρ) such that S i L n (A, ρ)=E n(A, ρ) whenever i ⩾ Bass-Serre dimension of A.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00533991
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  • 5
    Electronic Resource
    Electronic Resource
    Effect of the incubation conditions on the production of patulin by Penicillium griseofulvum isolated from wheat (1991)
    Springer
    Mycopathologia 115 (1991), S. 163-168 
    Details
    ISSN: 1573-0832
    Keywords: Penicillium griseofulvum ; patulin ; wheat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract Sixty-four wheat samples from Spanish flour factories were screened for patulin and patulin-producing moulds. None of them was found to contain any patulin, whereas samples experimentally contaminated with this toxin proved it to be highly unstable. On the other hand, Penicillium griseofulvum was the only in vitro patulin-producing species found (19 samples). Mould growth in the samples was investigated by using yeast-sucrose medium (YES) and high-performance liquid chromatography (HPLC) to measure the amounts of toxin produced during 40 day's incubation at 20 and 28°C. The highest yield rate of patulin was obtained between the 20th and 30th day of incubation; such a rate, however, was very low throughout the vigorous growth phase, during the first 20 days of incubation. The more appropriate temperature for incubation and patulin production was 28 °C. We also investigated the influence of other incubation conditions in the yield and found stationary dark cultures to be more efficient that shaken or fermentation cultures in YES medium. The best patulin yield achieved was 11.9 mg in the culture broth and 6.3 mg in the mycelium from 100 ml of medium.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00462220
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  • 6
    Electronic Resource
    Electronic Resource
    The effect of level of application on the residual value of superphosphate on a sandy soil in south-western Australia (1991)
    Springer
    Nutrient cycling in agroecosystems 29 (1991), S. 163-172 
    Details
    ISSN: 1573-0867
    Keywords: Superphosphate ; residual value ; sandy soil ; leaching of phosphorus ; lupins ; barley ; wheat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Agriculture, Forestry, Horticulture, Fishery, Domestic Science, Nutrition
    Notes: Abstract In a field experiment on deep, yellow, sandy soil near Badgingarra, Western Australia, the residual value of superphosphate applied one and two years previously was measured relative to freshly-applied superphosphate using yields of narrow-leafed lupin (Lupinus angustifolius), barley and wheat. In addition, soil samples were collected for measurement of bicarbonate-extractable soil P. This was also used to estimate the residual value of the superphosphate. For lupins and wheat, and for bicarbonate-extractable soil P, the residual value decreased with increasing level of application. For barley grain, the residual value was not significantly affected by the level of application. The decrease in residual value of superphosphate with increasing level of application is attributed to increased leaching of applied phosphorus (P) down the profile of the sandy soils as the level of application increases. This may reduce subsequent plant yields due to the delay in seedling roots reaching the P in the soil during the crucial early stages of plant growth. For lupins, the relationship between yield and the level of superphosphate applied was markedly sigmoidal. The relationship for wheat and barley was exponential. Consequently, at suboptimal levels of P application, lupins required about two to three times more P than wheat or barley to produce the same yield. However, lupins required less P to achieve near-maximum yield.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01048956
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  • 7
    Electronic Resource
    Electronic Resource
    A segment of rye chromosome 1 enhances growth and embryogenesis of calli derived from immature embryos of wheat (1991)
    Springer
    Plant cell reports 10 (1991), S. 148-151 
    Details
    ISSN: 1432-203X
    Keywords: wheat ; rye ; embryogenesis ; growth ; tissue culture
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary The influence of the short arm of rye chromosome 1 (1RS) from Secale cereale var. Imperial on the growth and differentiation of callus cultures from wheat Triticum aestivum var. Chinese Spring immature embryos was analysed. This chromosome arm was found to stimulate both embryogenesis and the rate of growth of calli. Recombinant lines carrying segments of 1RS were used to delineate the regions of 1RS responsible for the tissue culture effects. The enhancement of embryogenesis and the stimulation of growth were shown to be associated with two distinct genetic regions of the chromosome arm; the former is located between the centromere and the Sec 1 locus, while the latter is situated in the immediate vicinity of the Sec 1 locus.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00232047
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  • 8
    Electronic Resource
    Electronic Resource
    Clinical pharmacokinetics and tolerability of alpidem in healthy subjects given increasing single doses (1991)
    Springer
    European journal of clinical pharmacology 41 (1991), S. 369-374 
    Details
    ISSN: 1432-1041
    Keywords: Alpidem ; Anxiolytics ; pharmacokinetics ; tolerance ; metabolites ; sedation ; adverse events
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In a double-blind, placebo-controlled, crossover experiment in 21 healthy male volunteers, aged 19 to 27 y, the pharmacokinetics and tolerance of the new anxiolytic drug alpidem (SL80.0342) and its three major metabolites were studied after single doses of 25, 50, 100 and 200 mg. Plasma concentrations of alpidem (in 20 subjects) and metabolites (in 6 subjects) were measured by HPLC over a period of 54 h after dosing. Cmax, tmax and AUC(0–54) and, when possible, t1/2 were determined for alpidem and metabolites and the dose linearity of the parameters was investigated. The time to peak of alpidem was dose independent in most subjects and was short (1–4 h); the mean values at the four dosing levels were 1.9, 1.7, 1.6 and 1.8 h. The peak concentration increased with the dose, the mean values being 17, 34, 88 and 115 ng · ml−1, respectively. In 50% of the subjects cmax tended to stabilize between the 100 and 200 mg dose. Dose linearity was also present for the AUC, which plateaued between the 100 and 200 mg dose in only 3 out of 20 subjects; the mean AUC was 119, 281, 669 and 1117 ng · ml−1 · h, respectively. The apparent half-life of elimination appeared to be dose independent, mean values at the increasing dosing levels being 18.7, 19.9, 18,1 and 17.9 h. A similar relationship between the kinetics parameters and dose of the alpidem was observed for the metabolites SL83.0912, SL80.0522 and SL83.0725. The formation of metabolites was not saturated as their AUCs relative to corresponding alpidem AUCs were not dose related. Thus the kinetics of alpidem and its three major metabolites were linear after doses of 25 to 200 mg. The drug was well tolerated by most of the subjects. Sedation and dizziness occurred mainly after the 100 and 200 mg doses.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00314970
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  • 9
    Electronic Resource
    Electronic Resource
    Pharmacokinetics of caffeine in patients with decompensated type I and type II diabetes mellitus (1991)
    Springer
    European journal of clinical pharmacology 41 (1991), S. 449-452 
    Details
    ISSN: 1432-1041
    Keywords: Diabetes mellitus ; Caffeine ; pharmacokinetics ; P-450 mono-oxygenase
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Diabetes may alter the pharmacokinetics of aminopyrine and antipyrine, which are used to assess liver function. Caffeine has recently been used to test liver function, but the effect of diabetes on caffeine kinetics is not known. The kinetics of caffeine has been examined in patients with decompensated Type I and Type II diabetes and in two age- and sex-matched control groups. In both types of diabetes the apparent caffeine clearance, half-life, and apparent volume of distribution were similar to controls. It is concluded that decompensated diabetes does not influence the cytochrome P-448 mono-oxygenase system responsible for caffeine metabolism.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00626367
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  • 10
    Electronic Resource
    Electronic Resource
    Dopamine pharmacokinetics in critically ill newborn infants (1991)
    Springer
    European journal of clinical pharmacology 40 (1991), S. 593-597 
    Details
    ISSN: 1432-1041
    Keywords: Dopamine ; Newborns ; critically ill patients ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Dopamine is frequently used in critically ill newborn infants for treatment of shock and cardiac failure, but its pharmacokinetics has not been evaluated using a specific analytical method. Steady-state arterial plasma concentrations of dopamine were measured in 11 seriously ill infants receiving dopamine infusion, 5–20 μg · kg−1 · min−1, for presumed or proven sepsis and hypotensive shock. Steady-state concentrations of dopamine ranged from 0.013–0.3 μg/ml. Total body clearance averaged 115 ml · kg−1 · min−1. The apparent volume of distribution and elimination half life averaged 1.8 1 · kg−1 and 6.9 min, respectively. No relationship was observed between dopamine pharmacokinetics and gestational age, postnatal age or birthweight. Substantial interindividual variation was seen in dopamine pharmacokinetics in seriously ill infants, and plasma concentrations could not be predicted accurately from its infusion rate. Marked variation in clearance explains in part, the wide dose requirements of dopamine needed to elicit clinical response in critically ill newborn infants.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00279976
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  • 11
    Electronic Resource
    Electronic Resource
    The concentration-dependent disposition and kinetics of inulin (1991)
    Springer
    European journal of clinical pharmacology 40 (1991), S. 619-624 
    Details
    ISSN: 1432-1041
    Keywords: Inulin ; pharmacokinetics ; half life ; distribution ; concentration-dependent clearance ; healthy subjects ; chronic renal failure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The disposition of inulin was studied in 30 healthy male and 10 healthy female volunteers, and 10 patients with stable chronic renal failure (mean creatinine clearance 45 ml·min−1) following intravenous infusion of 70 mg·kg−1 over 5 min. Plasma concentrations fell rapidly initially but the rate of decline decreased continuously over 8 h and a linear terminal elimination phase could not be identified. Inulin was excreted rapidly by the subjects with normal renal function and 97.3% of the dose was recovered in the urine in 8 h. There was a progressive highly significant fall in the renal clearance of inulin after 2 h as plasma concentrations fell below about 150 mg·l−1. Six to 8 h after administration the clearance was less than 50% of the initial value in the healthy volunteers and the corresponding fall in the renal patients was 33%. The concentration-dependent renal clearance of inulin was confirmed in “step-up” and “step-down” constant infusion studies in which clearances were measured at mean plasma concentrations ranging from 35.2 to 186.7 mg·l−1. These studies virtually excluded time, changes in posture and urine flow rate as important factors. There was no statistically significant fall in clearance during the first 2 h and kinetic analysis was based on data obtained over this time. Under these conditions the mean plasma half life, volume of distribution (Vss) and total body clearance of inulin in the healthy males, healthy females and patients with chronic renal failure were 73.2, 65.5 and 172.4 min, 10.5, 9.6 and 8.81·70 kg−1 and 113.3, 111.5 and 43.3 ml·min−1·70 kg−1 respectively. There were no sex differences in any of the kinetic variables. The mechanism of the concentration-dependent clearance of inulin is unknown but the findings are consistent with saturable renal tubular reabsorption. Care is required with the use of inulin for measurement of the glomerular filtration rate by the single injection technique.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00279982
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  • 12
    Electronic Resource
    Electronic Resource
    Effect of ampicillin on mefloquine pharmacokinetics in thai males (1991)
    Springer
    European journal of clinical pharmacology 40 (1991), S. 631-633 
    Details
    ISSN: 1432-1041
    Keywords: Mefloquine ; ampicillin ; Thai subjects ; pharmacokinetics ; enterohepatic recycling ; drug interaction ; adverse effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The kinetics of a single oral dose of mefloquine given either alone or with ampicillin has been studied in 8 healthy Thai male volunteers. There was a significantly higher maximum whole blood mefloquine concentration after coadministration with ampicillin (1648 vs 1228 ng·ml−1), as well as a significantly reduced terminal half life (15.3 vs 17.7 days), mean residence time (20.1 vs 23.4 days) and volume of distribution at steady state (14.1 vs 19.4 l·kg−1). Although there was no significant change in the AUC from zero time to infinity, the AUC from zero time to 5 days was significantly increased by ampicillin (4.86 vs 3.27 μg·ml−1 day). These changes in mefloquine disposition after antibiotic treatment may be due both to an increase in fractional bioavailability and a reduction in the enterohepatic recycling of mefloquine.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00279985
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  • 13
    Electronic Resource
    Electronic Resource
    Lack of effect of multiple dose sucralfate on the pharmacokinetics of roxatidine acetate (1991)
    Springer
    European journal of clinical pharmacology 40 (1991), S. 637-638 
    Details
    ISSN: 1432-1041
    Keywords: Roxatidine acetate ; sucraflate ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00279987
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  • 14
    Electronic Resource
    Electronic Resource
    Pharmacokinetics of halofantrine and n-desbutylhalofantrine in patients with falciparum malaria following a multiple dose regimen of halofantrine (1991)
    Springer
    European journal of clinical pharmacology 41 (1991), S. 161-164 
    Details
    ISSN: 1432-1041
    Keywords: Halofantrine ; Malaria falciparum ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Halofantrine is a new blood schizontocidal drug used for the treatment of multidrug-resistant falciparum malaria. The pharmacokinetics of halofantrine (HAL) and its principal metabolite, N-desbutylhalofantrine (BHAL), was investigated in 6 adult male patients of Melanesian origin with uncomplicated falciparum malaria. The patients received 500 mg of halofantrine hydrochloride at times 0, 6 and 12 h (total 1.5 g). All patients responded to treatment with a mean parasite clearance time of 52.7 h and a mean fever clearance time of 33.8 h. The following kinetic parameters (mean values) were determined for HAL and BHAL, respectively: maximum plasma concentration (Cmax)=896 and 491 ng·ml−1; time to reach the Cmax (tmax)=15 and 56 h; elimination half-life (t1/2)=91 and 79 h and the mean residence time (MRT)=71 and 102 h. Based on the clinical response the plasma concentrations of HAL and BHAL were adequate for the treatment of uncomplicated falciparum malaria in the 6 patients.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00265910
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  • 15
    Electronic Resource
    Electronic Resource
    Fosinopril pharmacokinetics and pharmacodynamics in chronic ambulatory peritoneal dialysis patients (1991)
    Springer
    European journal of clinical pharmacology 41 (1991), S. 165-169 
    Details
    ISSN: 1432-1041
    Keywords: Fosinopril ; fosinoprilat ; CAPD ; ACE-inhibitor ; pharmacokinetics ; pharmacodynamics ; peritoneal dialysis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics and pharmacodynamics of fosinoprilat, the diacid of fosinopril sodium, a new angiotensin-converting enzyme (ACE) inhibitor, were investigated after the oral administration of 10 mg of fosinopril sodium to 6 chronic ambulatory peritoneal dialysis (CAPD) patients. The results from 1 patient are reported separately because of the presence of concomitant liver dysfunction. The mean t1/2, Cmax, tmax, and AUC values for 5 of the CAPD patients were 19.5 h, 202 ng·ml−1, 4.8 h, and 3.19 μg·h·ml−1, respectively. Values for 1 CAPD patient with liver dysfunction were t1/2 of 65.4 h, Cmax of 182 ng·ml−1, tmax of 9 h, and AUC of 18.1 μg·h·ml−1. Peritoneal clearance of fosinoprilat was negligible, ranging from 0.07 to 0.23 ml·min−1. Serum ACE activity remained significantly suppressed at 24 and 48 h after fosinopril sodium administration with mean decreases from baseline of 94.2% and 70.6%, respectively. ACE activity was suppressed to an even greater degree in the patient with liver dysfunction, remaining 97% inhibited 72 h after drug administration. Plasma renin activity (PRA) increased and plasma aldosterone concentrations decreased following drug administration. Mean arterial pressure did not change appreciably throughout the study. Dosage reductions may not be necessary in the majority of dialysis patients.
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    URL: http://dx.doi.org/10.1007/BF00265911
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  • 16
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    Pharmacokinetics of intravenous bisoprolol in obese and non-obese volunteers (1991)
    Springer
    European journal of clinical pharmacology 41 (1991), S. 171-174 
    Details
    ISSN: 1432-1041
    Keywords: Bisoprolol ; pharmacokinetics ; obesity ; blood flow
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of a single i. v. dose of dlbisoprolol 0.16 mg·kg−1 ideal body weight has been studied in 8 obese women (mean weight 91 kg; 161% of ideal body weight) and 8 non-obese women (51 kg; 94% of ideal body weight). Compared to the controls, the obese subjects showed an increase in the total apparent volume of distribution (Vz) (182 vs 135 1) and a decrease in Vz per kg body weight (2 vs 2.7 l·kg−1). There was a negative correlation between Vz l·kg−1 and the percentage of ideal body weight (r=−0.672). Total body clearance was increased, but t1/2 and renal clearance was unchanged. It is concluded that tissue diffusion of bisoprolol in obese subjects is limited, despite its lipophilicity, possibly because of alteration in the blood flow to adipose tissue produced by bisoprolol.
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    URL: http://dx.doi.org/10.1007/BF00265912
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  • 17
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    Steady state pharmacokinetics of hydrolysed bopindolol in young and elderly men (1991)
    Springer
    European journal of clinical pharmacology 41 (1991), S. 175-178 
    Details
    ISSN: 1432-1041
    Keywords: Bopindolol ; pharmacokinetics ; beta-adrenoceptor blocker ; age ; hydrolysed bopindolol
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Steady-state pharmacokinetic parameters of the new, long-acting beta-adrenoceptor blocker bopindolol have been measured in 17 young and 20 elderly healthy men. The t1/2β and the AUC(0→24 h) of hydrolysed bopindolol (the active metabolite) were both increased (40% and 26%, respectively) in the elderly subjects but tmax, Cmax and CL/f were not altered. However, after adjusting the parameters to allow for the different average body weights of the two groups, Cmax and CL/f became significantly different (+29% and −30%, respectively). AUC(0→24 h) was increased by 41%. The changes of up to 41% in pharmacokinetic parameters were smaller than the alterations of 50–100% usually seen when titrating doses of antihypertensive drugs. The clinical relevance of the effects was not examined, but similar changes have been reported for other beta-blockers which did not appear to be clinically relevant and did not affect the dosage required to treat hypertension.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00265913
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  • 18
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    Dose-dependent absorption and elimination of cefadroxil in man (1991)
    Springer
    European journal of clinical pharmacology 41 (1991), S. 179-183 
    Details
    ISSN: 1432-1041
    Keywords: Cefadroxil ; saturable absorption ; saturable renal tubular reabsorption ; cephalexin ; competitive inhibition ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetic behaviour of cefadroxil was dose-dependent in healthy male volunteers following the oral administration of single doses of 5, 15, and 30 mg · kg−1. As the dose of cefadroxil increased from 5 to 15 and 30 mg · kg−1, the peak plasma concentrations, normalized to 5 mg · kg−1, decreased significantly from 15.1 to 10.7 and 7.6 mg·l−1, while the corresponding normalized areas under the plasma concentration-time curves from 0 to 2 h decreased significantly from 1258 to 946 and 801 min·mg·l−1. When the same subjects were given 5 mg·kg−1 of cefadroxil together with 45 mg·kg−1 of cephalexin, the absorption of cefadroxil was slowed to a similar or greater extent than with the high dose of cefadroxil. Although the absorption rate decreased as the dose increased, the systemic availability of cefadroxil was essentially complete at all doses, as judged by the 24 h urinary recoveries of the antibiotic. Kinetic analysis of the plasma concentration-time curves gave the best fit with a zero-order followed by a first-order absorption process, consistent with saturable intestinal absorption of cefadroxil. The elimination rate of cefadroxil was directly related to dose and plasma concentrations, and the clearance at the dose of 5 mg·kg−1 was significantly increased by the simultaneous administration of high-dose cephalexin. The renal clearance of cefadroxil ranged from 98 ml·min·l−1 at total plasma cephalosporin (cefadroxil + cephalexin) concentrations less than 2.5 mg·l−1 to 156 mg·l−1 at concentrations greater than 40 mg·l−1. These findings are consistent with saturable active gastrointestinal absorption and renal tubular reabsorption of cefadroxil, with competitive inhibition of both processes by cephalexin.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00265914
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  • 19
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    Interaction of ORG 10172, a low molecular weight heparinoid, and digoxin in healthy volunteers (1991)
    Springer
    European journal of clinical pharmacology 41 (1991), S. 245-250 
    Details
    ISSN: 1432-1041
    Keywords: Org 10172 ; Digoxin ; heparinoid ; pharmacokinetics ; pharmacodynamics ; drug interactions
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Potential pharmacokinetic and pharmacodynamic interactions between a new low molecular weight heparinoid Org 10172 (bolus injection of 3250 anti-Xa units) and digoxin (0.25 mg once daily for 8 days) were studied in 6 healthy male volunteers using an open, randomised three-way cross-over design. Digoxin produced a slight increase in clearance of anti-Xa activity from 4.3 to 4.8 ml·min−1, while plasma anti-thrombin and thrombin generation inhibiting (TGI) activity remained unchanged. Digoxin did not affect the actions of Org 10172 on the clotting tests. In the presence of Org 10172 there was a reduction in the AUC of digoxin during one dosing interval after the seventh digoxin tablet from 20 to 17 ng·ml−1·h, and a significant reduction in the average serum digoxin conentration. Since renal digoxin clearance was not significantly changed this probably might be due to a change in the non-renal clearance of digoxin. Atrio-ventricular node conduction, as measured by PR-time intervals, remained unchanged during all three treatments. In conclusion, although the pharmacokinetics of Org 10172 and digoxin were slightly changed by the combination, it is probably safe to administer Org 10172 and digoxin simultaneously. The clinical relevance of the slight decrease in plasma anti-Xa activity levels cannot yet be defined.
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    Pharmacokinetics of tiaprofenic acid in children after a single oral dose (1991)
    Springer
    European journal of clinical pharmacology 41 (1991), S. 251-253 
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    ISSN: 1432-1041
    Keywords: Tiaprofenic acid ; children ; pharmacokinetics ; NSAID
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary. Twelve healthy children in three age groups anaesthetized for minor surgery were given a single oral dose of tiaprofenic acid (3 mg · kg−1) (TA). Seven blood samples and zero to 8 and 8 to 24 h urines were collected. TA concentrations in plasma and urine were measured by HPLC. No significant difference was found between the age groups in the kinetic parameters of TA and no correlation was found between these parameters and age; tmax=2.12h, Cmax=8.78mg · l−1, AUC(0→8 h) 33.9mg · h · l−1, AUC=39.3 mg · h · l−1, t1/2=2.35 h, Vz=0.319 l · kg−1, CL=0.094 l · h−1 · kg−1. Renal clearance was 14 ml · h−1. kg−1. 33% of the TA dose was recovered in the 24 h urine, 48% of which was conjugated, whereas in adults, TA is only found in urine as conjugates. The apparent plasma clearance was significantly higher (56%) than in 12 healthy adults given 1.5 mg · kg−1 TA. Volume of distribution and t1/2 did not significantly differ between children and adults. Since no relationship has been established between plasma TA and either efficacy or toxicity, a different dose regimen cannot be recommended in 3–11 year-old children from that in adults.
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    Pharmacokinetics of midazolam in children: comparative study of intranasal and intravenous administration (1991)
    Springer
    European journal of clinical pharmacology 41 (1991), S. 355-357 
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    ISSN: 1432-1041
    Keywords: Midazolam ; pharmacokinetics ; intranasal ; intravenous ; children ; bioavailability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Twelve children 1–5 y old were randomly assigned to receive midazolam 0.2 mg·kg−1 either by the intravenous (IV) or intranasal (IN) routes. After IN administration the rapid onset of absorption was observed (tmax 12 min). After both routes of administration the half-life was similar (2.2 h IN and 2.4 h IV). After IN administration the apparent plasma clearance and volume of distribution were about twice as high as after IV administration. The results are consistent with an estimated mean bioavailability of 55%.
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    Antipyrine kinetics in undernourished diabetics (1991)
    Springer
    European journal of clinical pharmacology 41 (1991), S. 359-361 
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    ISSN: 1432-1041
    Keywords: Diabetes ; Antipyrine ; undernutrition ; drug metabolism ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In developing countries diabetics frequently suffer from varying grades of malnutrition. The combined effect of malnutrition and non-insulin dependent diabetes (NIDDM) on the drug metabolising enzyme system has been evaluated using antipyrine as a protodrug. All the patients were under treatment and their plasma glucose values were within normal limits. The AUC of antipyrine was similar in all the groups. Although none of the kinetic parameters was altered in normal diabetics, the clearance of antipyrine was decreased and its half life was prolonged, with an increase in volume of distribution, in undernourished diabetics compared to undernourished controls. The results indicate that diabetes per se may not influence antipyrine kinetics when the blood glucose is well under control, but in the presence of undernutrition, it significantly alters the disposition of the drug.
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    Lack of effect of paracetamol on the pharmacokinetics and metabolism of codeine in man (1991)
    Springer
    European journal of clinical pharmacology 41 (1991), S. 379-382 
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    ISSN: 1432-1041
    Keywords: Codeine ; paracetamol ; codeine-6-glucuronide ; pharmacokinetics ; metabolism ; partial clearance ; drug interaction
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Plasma and urine concentrations of codeine and its measurable metabolites were determined by HPLC in six healthy subjects after a single 30 mg oral dose of codeine either alone or after 7 doses of 1 g paracetamol 8 hourly. After codeine alone, the t1/2 (h), AUC (μmol·l−1·h) and CLR (ml·min−1) for codeine were 2.2, 0.81, and 252 respectively. These were not significantly altered by paracetamol: 2.2, 0.84, and 291 respectively. For codeine-6-glucuronide the values were 2.4, 22.0, and 29.7 respectively. These were not significantly different from those after codeine plus paracetamol: 2.4, 21.9, and 39.6. There were no significant differences between the two treatments in the apparent partial clearances (ml·min−1) of codeine to morphine (88 codeine alone, 70 codeine plus paracetamol), to norcodeine (71 codeine alone, 88 codeine plus paracetamol), and to codeine-6-glucoronide (820 codeine alone, 1022 codeine plus paracetamol). The urinary excretion of codeine-6-glucuronide, morphine, norcodeine, and codeine were not significantly different between the two treatments.
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    Relationship between renal function and disposition of oral cefixime (1991)
    Springer
    European journal of clinical pharmacology 41 (1991), S. 579-583 
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    ISSN: 1432-1041
    Keywords: Cefixime ; renal failure ; pharmacokinetics ; volunteers ; adverse effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of cefixime following a single oral dose of 200 mg have been investigated in 6 normal subjects and in 22 patients with various degrees of renal insufficiency. Serum and urine samples were collected between 0 and 72 h and were subjected to two methods of analysis: bioassay and HPLC. There was a linear relationship between the two sets of results from 228 samples. This result suggests that none of the metabolites, which may accumulte in uraemic patients, has antibacterial activity. In normal subjects, the peak serum level (Cmax) was 2.50 μg·ml−1 at 2.83 h (tmax); the apparent elimination half-life (t1/2) was 3.73 h; the apparent total body clearance (CL·f−1) was 154 ml·min−1, the mean renal clearance (CLR) was 39.1 ml·min−1 and the apparent fraction of the dose recovered in 24 h urine was 0.22. In uraemic patients, Cmax and tmax were slightly increased and t1/2 was increased to 12–14 h in patients with an endogenous creatinine clearance below 20 ml·min−1. The apparent volume of distribution was decreased. Apparent total and renal clearances were lower in proportion to the degree of renal insufficiency. Linear relationships were found between CL/f, CLR and creatinine clearance (CLCR). The findings suggest that the dose of cefixime needs to be reduced only in patients with severe renal failure.
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    Pharmacokinetics of chlormezanone in elderly patients (1991)
    Springer
    European journal of clinical pharmacology 41 (1991), S. 603-607 
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    ISSN: 1432-1041
    Keywords: Chlormezanone ; pharmacokinetics ; elderly
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of Chlormezanone (CM) has been determined after a single oral dose of 400 mg CM in 5 young volunteers (28 y) and in 8 elderly patients (79 y). In the young subjects, CM was rapidly absorbed and distributed, and was slowly eliminated with a half-life of 38 h major metabolites were not detected in plasma or urine. Only 3% of CM was excreted unchanged in urine. In elderly patients absorption was delayed but not reduced; the Cmax and AUC did not differ from those in younger subjects, the elimination rate was reduced compared to the younger subjects (mean 54 h). The increase was in part related to the reduction in renal function and metabolism observed in aging. However, the change in pharmacokinetics was moderate and no adjustment in dosage seems necessary for treatments of limited duration in elderly patients.
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    Clinical chronopharmacology of oral sustained-release isosorbide-5-mononitrate in healthy subjects (1991)
    Springer
    European journal of clinical pharmacology 40 (1991), S. 71-75 
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    ISSN: 1432-1041
    Keywords: Isosorbide-5-mononitrate ; sustained-release formulation ; pharmacokinetics ; cardiovascular effects ; chronopharmacology ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In 10 healthy male subjects the pharmacokinetics and haemodynamic effects of sustained-release isosorbide-5-mononitrate 60 mg (IS-5-MN) were studied after oral administration at two different times in the day (08.00 h and 20.00 h). Effects on blood pressure and heart rate after 3 min standing upright were measured in relation to the individual circadian control values. The pharmacokinetic parameters (Cmax, tmax, AUC, t1/2) did not differ after morning and after evening dosing, tmax being 5.2 h and 4.9 h, respectively. In contrast, the cardiovascular effects of IS-5-MN were clearly circadian phase-dependent. The maximum decrease in blood pressure decrease and increase in heart rate occurred significantly earlier after the evening (BPsys 2.8 h; BPdia 2.9 h; HR 3.8 h) than after the morning dose (BPsys 5.0 h; BPdia 6.0 h; HR 5.2 h). Thus, the peak haemodynamic effects coincided with the peak drug concentration after the morning dose, whereas the peak effect was in advance of the peak drug concentration after the evening dose of IS-5-MN. The data provide evidence of circadian phase-dependency in the dose-response relationship of oral IS-5-MN.
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    Pitfalls of pharmacokinetic dosage guidelines in renal insufficiency (1991)
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    European journal of clinical pharmacology 40 (1991), S. 87-93 
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    ISSN: 1432-1041
    Keywords: Pharmacotherapy ; renal insufficiency ; pharmacokinetics ; renal drug elimination ; drug monitoring ; dosage guidelines
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary As the renal elimination of most drugs is closely correlated with the endogenous creatinine clearance, it is possible to use this parameter of kidney function to adjust drug dosage in renal failure. However, this simple procedure neglects possible changes in the volume of distribution, plasma protein binding, drug metabolism, intestinal absorption, and pharmacodynamics in renal insufficiency, as well as the occurrence of biologically active drug metabolities. Because of these uncertainties in critical cases the validity of the dosage calculated using the creatinine clearance should be checked by clinical surveillance and measurements of drug blood concentrations. Further, pharmacokinetic dosage guidelines based on the individual creatinine clearance may not be applicable to diuretics and drugs which have markedly differing kinetics of pharmacodynamic effects and blood levels.
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    Pharmacokinetics of the anti-inflammatory drug ximoprofen in healthy subjects and in disease states (1991)
    Springer
    European journal of clinical pharmacology 40 (1991), S. 101-106 
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    ISSN: 1432-1041
    Keywords: Ximoprofen ; pharmacokinetics ; normal subjects ; hepatic disease ; renal disease
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of ximoprofen, a potent new non-steroidal anti-inflammatory agent, has been investigated in normal healthy subjects and in patients with hepatic or renal disease. After intravenous infusion of 22.8 mg to healthy subjects, plasma ximoprofen concentrations declined in a polyexponential manner with a terminal phase half-life of 1.9 h. The systemic clearance of ximoprofen was 115 ml·min−1 and the volumes of distribution were 18.0 l Vz and 13.8 l Vss. Ximoprofen was 80–90% bound to plasma proteins. The systemic availabilities (f) of orally and rectally administered doses of 30 mg of ximoprofen were 98% and 56% respectively and, in the case of the rectal dose, absorption appeared to be prolonged leading to “flip-flop” kinetics. After single oral doses of 30 mg of ximoprofen to patients with hepatic disease, half-life (2.2 h), peak plasma concentrations (1.55 μg·ml−1 cf 1.04 μg·ml−1 in healthy subjects) and areas under the curve (6.12 μg·h·ml−1 cf 3.54 μg·h·ml−1 in healthy subjects) were significantly different from those in healthy subjects. After single oral doses of 30 mg of ximoprofen to patients with renal disease, pharmacokinetic parameters of half-life (4.0 h), mean residence time (6.0 h) and area under the curve (9.2 μg·h·ml−1) were significantly different from those in healthy subjects. There were no significant differences in pharmacokinetic parameters between patients having differing degrees of renal disease. These data nevertheless suggest that accumulation of ximoprofen in hepatic or renal disease would be of slight or negligible clinical relevance and that no alteration of the dose regimen (up to 15 mg twice daily) may be required when ximoprofen is administered in these disease states.
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    CSF Baclofen levels after intrathecal administration in severe spasticity (1991)
    Springer
    European journal of clinical pharmacology 40 (1991), S. 363-365 
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    ISSN: 1432-1041
    Keywords: Baclofen ; severe spasticity ; pharmacokinetics ; CSF ; intrathecal injection
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetic parameters in the CSF of baclofen given to 4 patients as an intrathecal bolus are reported. Considerable inter-individual variability in the parameters was observed. The elimination half-life ranged from 0.9 to 5 h and the clearance from 0.013 to 0.08 l·h−1. In order to optimize treatment, it is suggested that CSF baclofen levels be matched to changes in Hoffman's monosynaptic reflex (H reflex).
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    Evaluation of proposed sulphoxidation pathways of carbocysteine in man by HPLC quantification (1991)
    Springer
    European journal of clinical pharmacology 40 (1991), S. 387-392 
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    ISSN: 1432-1041
    Keywords: Carbocysteine ; pharmacogenetics ; drug metabolism ; sulphoxidation ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary A quantitative study has been made of the metabolism of S-carboxymethyl-L-cysteine (CMC) and its sulphoxides in volunteers by HPLC. Precolumn derivatization was applied prior to gradient reversed phase HPLC separation and fluorescence detection. For CMC and its metabolites containing a primary amino group the reagent 9-fluorenylmethylchloroformate was used. The other metabolites of CMC were derivatized at their carboxylic group with 1-pyrenyldiazomethane to give stable fluorescent products. Urine samples were collected for 8 h after oral administration of 1.125 g CMC to 33 healthy volunteers. Elimination of CMC in urine as sulphoxides did not account for more than 1% of the dose in any of the volunteers. Thus, CMC-sulphoxide metabolites are not quantitatively important. Recovery of the original substance in 8-hour urines ranged from 10 to 30% and a further 2 to 20% was recovered as the metabolite thiodiglycolic acid. Oral doses of 0.19, 1.125, and 2.25 g CMC in a second group of 12 healthy volunteers did not reveal dose dependence of the urinary excretion of the sulphoxides or of thiodiglycolic acid. Serum concentration-time-curves of CMC, (S)- and (R)-CMC sulphoxide were measured in a group of 9 healthy volunteers. The CMC sulphoxides in serum reached 1.5% of the parent substance after 4 hours. The ratio of CMC to its sulphoxide metabolites was similar in serum and urine. Pharmacogenetic polymorphism of sulphoxidation was not confirmed by the specific HPLC methods used.
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    Interaction of metoprolol with lorazepam and bromazepam (1991)
    Springer
    European journal of clinical pharmacology 40 (1991), S. 405-409 
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    ISSN: 1432-1041
    Keywords: Metoprolol ; lorazepam ; bromazepam ; interaction ; psychomotor tests ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The interaction between metoprolol and bromazepam and lorazepam was studied in 12 healthy male volunteers aged 21–37 years. Metoprolol had no significant effect on the pharmacokinetics of bromazepam or lorazepam. However, bromazepam AUC was 35% higher in the presence of metoprolol. Bromazepam enhanced the effect of metoprolol on systolic blood pressure but not on diastolic blood pressure or pulse rate. Lorazepam had no effect on either blood pressure or pulse. Metoprolol did not enhance the effect of bromazepam on the psychomotor tests used in this study. Metoprolol caused a small increase in critical flicker fusion threshold with lorazepam but had no effect on the other tests. Lorazepam (2 mg) was more potent than bromazepam (6 mg) in the doses used in this study. The interaction of metoprolol with bromazepam and lorazepam is unlikely to be of clinical significance. No change in dose is necessary when using these drugs together.
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    Pharmacokinetics of ibuprofen in febrile children (1991)
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    European journal of clinical pharmacology 40 (1991), S. 427-428 
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    ISSN: 1432-1041
    Keywords: Ibuprofen ; children ; fever ; pharmacokinetics ; adverse effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Ibuprofen may be an alternative to acetaminophen to control fever in children but little is known about its pharmacokinetics in pediatric patients. We studied 17 patients (age 3–10 yr) with fever; the most prevalent diagnoses were streptococcal pharyngitis and otitis media. Ibuprofen liquid was given as a single dose, 5 mg/kg (9 patients) or 10 mg/kg (8 patients). Multiple blood samples were collected over 8 hours and analyzed by HPLC. The maximum observed serum concentrations of ibuprofen ranged from 17–42 μm·ml−1 at 5 mg·kg−1 and 25–53 μm·ml−1 at 10 mg·kg−1 doses. Pharmacokinetics did not appear to be affected by ibuprofen dose. Mean tmax, oral clearance and elimination half life were 1.1 h, 1.2 ml·min−1·kg−1, and 1.6 h, respectively in patients at 5 mg·kg−1 doses; the corresponding values were 1.2 h, 1.4 ml·min−1·kg−1, and 1.6 h in those receiving 10 mg·kg−1 doses. There was no relationship between age and ibuprofen kinetics. No adverse effects occurred in any patients. These data suggest that ibuprofen pharmacokinetics may not be affected by dose between 5 and 10 mg/kg or age between 3 and 10 years.
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    Disposition of epirubicin and metabolites with repeated courses to cancer patients (1991)
    Springer
    European journal of clinical pharmacology 40 (1991), S. 481-487 
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    ISSN: 1432-1041
    Keywords: Epirubicin ; pharmacokinetics ; plasma concentrations ; cancer patients
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Thirteen cancer patients were studied following a total of 41 courses of epirubicin (EPI) (38–50 mg·m−2, mean 49.2 mg·m−2, administered by a 60 min infusion), together with other cancer chemotherapeutic agents. The aim was to consider the disposition of EPI and metabolites following subsequent courses as it has been reported that doxorubicin (the 4′-epimer parent of EPI) clearance is increased following the first administration. We have observed that EPI-glucuronide accounted for a mean 78.0%, epirubicinol 0.2% and epirubicinol-glucuronide 19.3% and that parent EPI accounted for only 2.4% of the EPI-compounds measured (mean of all patients and courses) for the 3 h period immediately following the infusion. These data confirm the rapid metabolism of EPI and the dominance of the glucuronidation metabolite pathway (which is not available to doxorubicin) and are compared with the metabolite profile observed in other reports. Large inter- and intra-individual variability in area under the plasma concentration/time curve were observed with no clear evidence of any consistent directional trend for such fluctuations, suggesting that factors contributing to EPI disposition are multivariate.
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    Polymorphic flecainide disposition under conditions of uncontrolled urine flow and pH (1991)
    Springer
    European journal of clinical pharmacology 40 (1991), S. 155-162 
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    ISSN: 1432-1041
    Keywords: Flecainide ; sparteine/debrisoquine polymorphism ; metabolism ; enantiomers ; pharmacokinetics ; stereoselectivity
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of R- and S-flecainide have been determined in five poor (PM) and five extensive (EM) metabolisers of sparteine/debrisoquine under conditions of uncontrolled urine flow and pH. The half-lives of R- and S-flecainide in PMs (R 19.3 h; S 16.1 h) were approximately twice those observed in EMs (R 8.8 h; S 9.1 h). The apparent oral clearances of R- and S-flecainide were lower in PMs (R 313 ml·min−1; S 379 ml·min−1) than in EMs (R 783 ml·min−1; S 828 ml·min−1). The renal clearance, however, was comparable for both enantiomers in both EMs and PMs, and therefore the phenotypic differences in flecainide disposition observed must be due to differences in metabolic clearance. The nonrenal clearance of both enantiomers was significantly lower in poor (R 123 ml·min−1; S 201 ml·min−1) relative to extensive metabolisers (R 533 ml·min−1; S 586 ml·min−1). The partial clearance to the two major metabolites meta-O-dealkylated flecainide (MODF) and the meta-O-dealkylated lactam of flecainide (MODLF) was significantly lower in poor (62 ml·min−1) than extensive (267 ml·min−1) metabolisers. The impairment in flecainide metabolism in poor metabolisers of sparteine/debrisoquine has therefore been confirmed. Under conditions reflecting the clinical situation the difference in disposition between EMs and PMs would be considerable. However, it may be predicted that at standard doses concentrations greater than 1000 ng·ml−1 would not be attained in the PMs studied. The serum protein binding of R- and S-flecainide was studied in each subject and no differences between the enantiomers or the phenotypes were observed (Free fraction EM: R 0.43; S 0.42; PM R: 0.46; S: 0.46). Enantioselective disposition was noted in all PMs studied, due to a significantly lower nonrenal clearance of the R-enantiomer. In extensive metaboliser subjects, considerable interindividual variation in the enantioselective disposition of flecainide was noted, ranging from metabolism favouring either enantiomer to the absence of any selectivity.
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    The relationships between dose and concentration of tolbutamide and insulin and glucose responses in patients with non-insulin-dependent diabetes (1991)
    Springer
    European journal of clinical pharmacology 40 (1991), S. 163-168 
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    ISSN: 1432-1041
    Keywords: Tolbutamide ; diabetes mellitus ; non-insulin dependent ; pharmacokinetics ; pharmacodynamics ; glucose ; insulin
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary It is uncertain how the hypoglycaemic effect of sulphonylureas varies with drug concentration in patients with non-insulin-dependent diabetes mellitus. The interrelationship of tolbutamide dosage and concentration, and glucose and insulin concentrations were therefore examined in 54 out-patients (the observational group) and in 20 patients studied under controlled conditions (the experimental group). In the observational group, tolbutamide concentration depended significantly on the daily dose, time from dose to sampling, body weight, and age. Blood glucose and insulin concentration were related, but were independent of tolbutamide concentration. In the experimental group, peak, but not pre-dose, tolbutamide concentration, depended on dose and on body mass index. Fasting and maximum post-prandial blood glucose concentration were positively correlated with maximum tolbutamide concentration, probably because tolbutamide dosage was highest in those with the poorest response. In the subset with a fasting blood glucose concentration of less than 8 mmol·l−1, neither glucose nor insulin concentrations depended significantly on tolbutamide concentrations. Tolbutamide concentration does not directly determine hypoglycaemic response in outpatients, and therapeutic monitoring of drug concentrations would not improve the management of such patients.
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    Effect of duration of levodopa/decarboxylase inhibitor therapy on the pharmacokinetic handling of levodopa in elderly patients with idiopathic Parkinson's disease (1991)
    Springer
    European journal of clinical pharmacology 41 (1991), S. 459-462 
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    ISSN: 1432-1041
    Keywords: Levodopa/decarboxylase inhibitor ; Parkinson's Disease ; pharmacokinetics ; duration of therapy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary We address, from a pharmacokinetic viewpoint, the important question of why some patients with clinical idiopathic Parkinson's disease experience a fall off in benefit from levodopa maintenance therapy. Thirteen such patients, of mean age 78 y, without overt fluctuations in motor control in temporal relation to dosing with a levodopa/decarboxylase inhibitor combination, were studied. Levodopa (currently 400 to 800 mg daily) had been started at between 61 and 81 y of age, the mean duration of therapy being 54 months. Plasma concentrations of levodopa and its peripheral metabolite, 3-0-methyldopa, were measured before a morning dose of levodopa (100 mg)/carbidopa (25 mg) and at hourly intervals for 6 h after. There was a significant negative regression between duration of levodopa therapy (but not age or severity of disease) and the area under the plasma concentration/time curve (AUC) for levodopa attributed to the test dose. A significant negative regression was also seen of duration of therapy on the dose absorbed per unit distribution volume, but not on the elimination rate constant, indicating a decrease in bioavailability and/or an increase in distribution volume with duration. There was a tendency for the plasma 3-0-methyldopa concentration, standardised for daily dose, [30MD], to increase with duration of therapy. Although, the regression of duration on [30MD] did not reach statistical significance, that on the ratio, [30MD]/AUC, did so at the 0.01 level. The amount by, and time for which, the plasma levodopa concentration exceeds any critical threshold for the competitive active uptake process into the brain may thus decrease with duration of therapy. This may explain in part the limited reversal of the neurological deficit, which is more typical of later onset Parkinsonism, and, possibly, the decrement in biological half time with duration of therapy, typical of early onset disease. 3-0-Methyldopa is known to compete for active uptake with levodopa; the ratio, [30MD]/AUC, may be a measure of this competition. Intrinsic activity of neuronal uptake mechanisms, capacity of the basal ganglia for storage of dopamine, and post synaptic neuronal activity may, of course, also be determinants of clinical outcome.
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    Elimination of flecainide as a function of urinary flow rate and pH (1991)
    Springer
    European journal of clinical pharmacology 41 (1991), S. 61-63 
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    ISSN: 1432-1041
    Keywords: Flecainide ; dose adjustment ; urinary pH ; urinary flow rate ; renal elimination ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In order to evaluate the influence of urinary flow rate at different pH values on the pharmacokinetics of the basic antiarrhythmic drug flecainide 7 healthy men received 50 mg flecainide under 4 different conditions: 1. acidic urine (pH 5) and a high fluid load (125 ml · h−1) 2. acidic urine (pH 5) and a low fluid load (25 ml · h−1) 3. alkaline urine (pH 8) and a high fluid load (125 ml · h−1) 4. alkaline urine (pH 8) and a low fluid load (25 ml · h−1) At acidic pH the half-life, the amount of unchanged drug in the urine (Ae), renal clearance (CLR) and area under the curve (AUC) were independent of the fluid load. At alkaline pH Ae (5.8 vs 2.6 mg) and CLR (73 vs 33 ml · min−1) were significantly affected by fluid load (high vs low), whereas half-life and AUC were not different (15.7 vs 16.0 h, 1480 vs 1540 ng · ml−1 · h). When comparing acidic and alkaline urinary pH conditions, half-life, Ae, CLR, and AUC were different. For a high fluid load the values at acidic vs alkaline pH were half-life 10.0 vs 15.7 h; Ae 15.9 vs 5.8 mg; CLR 288 vs 73 ml · min−1; AUC 976 vs 1480 ng · ml−1 · h. For a low fluid load the corresponding values at acidic vs alkaline pH were half-life 10.1 vs 16.0 h; Ae 15.9 vs 2.6 mg; CLR 267 vs 33 ml · min−1; AUC 1045 vs 1540 ng · ml−1 · h. It is concluded that urinary pH affects flecainide pharmacokinetics independently of urinary flow rate, and that a high flow enhances the elimination of flecainide only with an alkaline urine. This effect of flow rate does not appear to be of clinical relevance.
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    Kinetics of cholinesterase inhibition by eptastigmine in man (1991)
    Springer
    European journal of clinical pharmacology 41 (1991), S. 83-84 
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    ISSN: 1432-1041
    Keywords: Eptastigmine ; cholinesterase inhibitor ; Alzheimer's disease ; pharmacokinetics ; adverse effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
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    URL: http://dx.doi.org/10.1007/BF00280116
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    Pharmacokinetic investigation of oral and IV dihydroergotamine in healthy subjects (1991)
    Springer
    European journal of clinical pharmacology 41 (1991), S. 597-602 
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    ISSN: 1432-1041
    Keywords: Dihydroergotamine mesilate ; pharmacokinetics ; urinary excretion ; prolonged half-life ; deep compartment ; RIA ; adverse effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary A new radioimmunoassay (RIA) for the specific measurement of dihydroergotamine (DHE), sufficiently sensitive for the determination of low plasma concentrations, has been used to investigate the pharmacokinetics of unchanged DHE. In a randomized crossover trial, eight healthy male volunteers received single doses of DHE 5 mg, 10 mg and 20 mg orally and 0.1 mg and 0.5 mg intravenously. It was possible to determine plasma concentrations and urinary excretion of DHE over the following 48 h. A long terminal plasma elimination phase of unchanged DHE (half-life 15 h) was found. A similar terminal elimination half-life was also calculated from urine data. The multi-exponential decline in plasma DHE with a long terminal half-life suggests that distribution into a deep compartment contributes to the long-lasting effect of the drug. Plasma protein binding was 93%. Despite extensive tissue distribution (Vz=33 l/kg) and a high plasma clearance (CLP=2l/min), dose-independent linear pharmacokinetics was observed. The present assay was at least 20-times more specific than the polyvalent RIA used previously and appears suitable to explore the pharmacokinetics of unchanged DHE in patients on low-dose therapy. The long terminal elimination half-life of DHE only reported previously in studies using 3H-labelled drug, and considered to be due to metabolites, was also true for the parent compound. This, in addition to the sustained pharmacological activity of the 8′-hydroxy metabolite already shown, provides a further explanation for the long duration of action of DHE in animals and man.
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    Effect of piperine on bioavailability and pharmacokinetics of propranolol and theophylline in healthy volunteers (1991)
    Springer
    European journal of clinical pharmacology 41 (1991), S. 615-617 
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    ISSN: 1432-1041
    Keywords: Piperine ; Propranolol ; Theophylline ; pharmacokinetics ; drug interaction
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effect of piperine on the bioavailability and pharmacokinetics of propranolol and theophylline has been examined in a crossover study. Six subjects in each group received a single oral dose of propranolol 40 mg or theophylline (150 mg) alone or in combination with piperine 20 mg daily for 7 days. An earlier tmax and a higher Cmax and AUC were observed in the subjects who received piperine and propranolol. It produced a higher Cmax, longer elimination half-life and a higher AUC with theophylline. In clinical practice, the enhanced systemic availability of oral propranolol and theophylline could be exploited to achieve better therapeutic control and improved patient compliance.
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    Inhibition of ex-vivo PAF-induced platelet aggregation by the PAF-antagonist RP 48740: relationship to plasma concentrations in healthy volunteers (1991)
    Springer
    European journal of clinical pharmacology 41 (1991), S. 141-145 
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    ISSN: 1432-1041
    Keywords: Platelet activating ; Factor RP 48740 ; platelet aggregation ; PAF-antagonist ; dose-response relationship ; adverse effects ; pharmacokinetics ; dose-response relationship
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary RP 48740, 3-(3-pyridyl)-1H,3H-pyrrolo [1,2-c] thiazole-7-carboxamide, a specific competitive PAF-receptor antagonist in vitro, was given to 29 healthy male volunteers for 7 days. Plasma drug concentrations and exvivo PAF-induced platelet aggregation were assessed on Days 1, 4, and 7. RP 48740 had linear pharmacokinetics after single and repeated doses. It caused stable inhibition of PAF-induced platelet aggregation in a dose-dependent manner. The effect disappeared within 24 h, even after 7 days of repeated doses. The effect of RP 48740 displayed a sigmoidal relation to the plasma drug concentration; I50 2.3 (0.3) mg·l−1. There were no clinical or biological adverse reactions to RP 48740 during the study.
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    Enantioselective steady-state kinetics of unbound disopyramide and its dealkylated metabolite in man (1991)
    Springer
    European journal of clinical pharmacology 41 (1991), S. 481-484 
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    ISSN: 1432-1041
    Keywords: Disopyramide ; pharmacokinetics ; protein binding ; enantiomers ; metabolism ; metabolite kinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Disopyramide is provided as a racemic mixture of R and S enantiomers, which have different pharmacodynamic and pharmacokinetic characteristics. Five volunteers were given racemic disopyramide 100 mg and 200 mg t.d.s. in a cross-over design. Plasma and urine concentrations of disopyramide and its active metabolite monodesisopropyl-disopyramide (MND) were determined at steady state by an enantioselective HPLC method. Unbound drug in plasma was measured after ultrafiltration. There was enantioselective clearance of unbound disopyramide (0.39 l.h−1.kg−1 for R-disopyramide and 0.58 l.h−1.kg−1 for S-disopyramide after 100 mg t.d.s.). The enantioselectivity was due to differences in the metabolism of disopyramide to MND and in further non-renal clearance, and the renal clearance of disopyramide was not enantioselective. The in vivo protein binding of disopyramide, which was saturable for both enantiomers, was also enantioselective. The difference in binding of the two enantiomers was explained by a difference in apparent binding capacity rather than in apparent binding affinity. The renal clearance of S-MND was significantly higher than R-MND (0.29 and 0.19 l.h−1.kg−1, respectively, after 100 mg t.d.s.). The renal clearance of MND also showed a tendency to saturation at higher concentrations.
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    Pharmacokinetics of oral salbutamol controlled-release in Asian patients with asthma (1991)
    Springer
    European journal of clinical pharmacology 41 (1991), S. 495-496 
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    ISSN: 1432-1041
    Keywords: Asthma ; Salbutamol ; Asians ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Using a double blind, double dummy crossover design, single dose and steady state pharmacokinetics of oral controlled release (SCR) salbutamol 4 mg and 8 mg tablets b. d. has been studied in 8 Asian patients. Plasma salbutamol was measured over 12 h. In 8 patients the single dose mean Cmax was 4.2 ng·ml−1 and 7.7 ng·ml−1 after 4 and 8 mg, respectively. In 5 patients the steady state mean Cmax, Cmin and tmax were 8.1 ng·ml−1 and 4.7 ng·ml−1 and 6 h for the 4 mg tablets and 14.1 ng·ml−1 and 7.1 ng·ml−1 and 4 h for the 8 mg tablets. It is concluded that both doses of SCR show features of controlled release and that they produced a relatively constant plasma level of salbutamol in Asian patients.
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    Relation between plasma concentration and clinical efficacy after sublingual single dose apomorphine in Parkinson's disease (1991)
    Springer
    European journal of clinical pharmacology 41 (1991), S. 493-494 
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    ISSN: 1432-1041
    Keywords: Parkinson's disease ; Apomorphine ; pharmacokinetics ; adverse effect ; on-off effect
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Five patients with Parkinson's disease were given a single sublingual dose of apomorphine in 3 mg tablets (2 patients received 18 mg and 3 patients took 39 mg). The therapeutic effect appeared within 33.0 min and lasted 137 min. There was a significant correlation between peak concentration, area under the curve, dose (mg/kg) and the duration of the therapeutic effect.
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    Therapeutic monitoring of cyclosporin — an update (1991)
    Springer
    European journal of clinical pharmacology 41 (1991), S. 273-283 
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    ISSN: 1432-1041
    Keywords: Cyclosporin A ; therapeutic monitoring ; assay techniques ; pharmacokinetics ; dose-response relationships
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The success of organ transplantation is closely related to clinical use of the immunosuppressive drug cyclosporin (CsA). The dosage of CsA is complicated by the large intra- and interindividual variability in its pharmacokinetics, as well as by the narrow concentration range between insufficient immunosuppression and toxicity. Potential sources of error in the sampling procedure and the advantages and disadvantages of the available analytical methods are discussed. Traditionally, 12 or 24 hour trough concentrations of CsA are monitored. Recently, peak concentrations or estimation of AUCs by a limited sampling strategy have been tried to improve the relatively weak concentration-effect and concentration-toxicity relationships found with trough CsA concentration monitoring. Studies of the CsA concentration-effect relationships for various treatment indications are reviewed.
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    Verapamil in the prophylaxis of bronchial asthma (1991)
    Springer
    European journal of clinical pharmacology 41 (1991), S. 317-319 
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    ISSN: 1432-1041
    Keywords: Asthma ; Verapamil ; histamine-induced bronchoconstriction ; calcium antagonists ; plasma levels ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary A single oral dose of verapamil 80 mg was shown significantly to inhibit histamine-induced bronchoconstriction in 8 out of 16 asthmatic subjects (maximum increase in PD20FEVHi 416%). There was still significant protection (Δ PD20FEV1Hi〉100%) in the responders 5 h after the oral dose. The relationship of the bronchoprotective effect to the plasma level of verapamil was also examined. Responders and non-responders did not differ significantly in the peak plasma level or the time course of the plasma verapamil concentration. The protective effect was not correlated with the peak plasma level of verapamil or with the baseline bronchial hyperreactivity.
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    Pharmacokinetics of paroxetine in patients with cirrhosis (1991)
    Springer
    European journal of clinical pharmacology 41 (1991), S. 351-354 
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    ISSN: 1432-1041
    Keywords: Paroxetine ; Cirrhosis ; pharmacokinetics ; multiple-dose study ; adverse effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In a 14-day multiple-dose study the pharmacokinetics of paroxetine was investigated in 12 patients with alcoholic cirrhosis and in 6 subjects without liver disease. The dose of 20–30 mg paroxetine daily was adjusted to the reduction in liver function, as assessed by the galactose elimination capacity. Accordingly, all but two of the cirrhotic patients received 20 mg, while all six control subjects received 30 mg. Dose-corrected, trough drug concentration at steady state (CSS min) and dose-corrected AUC24h were significantly higher in the patients with liver diseases than in the control subjects [3.4 vs 1.5 ng · ml−1 per mg paroxetine and 89 vs 43 h (ng) · ml−1 per mg paroxetine]. The elimination t1/2 was prolonged [83 vs 36 h], but the difference was not statistically significant, and the cirrhotic patients were still able to clear almost all the paroxetine by metabolism. All but two patients with cirrhosis experienced nausea during the first two or three days after the first dose, while none of the controls had this symptom. The study showed slower elimination of paroxetine and consequently higher plasma levels in patients with cirrhosis, suggesting that in the latter the dose of paroxetine should be in the lower end of the therapeutic range.
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    Dose-dependent pharmacokinetics of benzoic acid following oral administration of sodium benzoate to humans (1991)
    Springer
    European journal of clinical pharmacology 41 (1991), S. 363-368 
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    ISSN: 1432-1041
    Keywords: Benzoic acid ; hippuric acid ; pharmacokinetics ; hyperammonaemia ; ureagenesis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Plasma concentration-time data for benzoic and hippuric acids and urinary excretion-time data for hippuric acid were analyzed simultaneously after oral doses of 40, 80 or 160 mg/kg sodium benzoate administered at least one week apart to 6 healthy subjects. The mean AUCs of benzoic acid after the doses of 80 and 160 mg/kg of sodium benzoate were 3.7- and 12.0-times greater, respectively, than after 40 mg/kg. However, the mean AUC of hippuric acid was roughly proportional to the benzoate doses. The observed data were explained by a one-compartment model with first-order rate absorption and Michaelis-Menten elimination of benzoic acid, together with a one-compartment model with first-order elimination for hippuric acid. Although the maximum rate of biotransformation of benzoic acid to hippuric acid varied between 17.2 and 28.8 mg·kg−1·h−1 among the six individuals, the mean value (23.0 mg·kg−1·h−1) was fairly close to that provided by daily maximum dose (0.5 g·kg−1·day−1) recommended in the treatment of hyperammonaemia in patients with inborn errors of ureagenesis. The individual maximum rate of metabolism can be estimated from the urinary excretion rate of hippuric acid 1.5 to 3 h after the single oral dose of 80 to 160 mg·kg−1 sodium benzoate. The justification of this concept requires further studies in patients with inborn errors of urea synthesis.
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    Pharmacokinetics of intramuscular nicomorphine and its metabolites in man (1991)
    Springer
    European journal of clinical pharmacology 41 (1991), S. 375-378 
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    ISSN: 1432-1041
    Keywords: Nicomorphine ; 6-nicotinoylmorphine ; morphine ; intramuscular administration ; metabolism ; absorption ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary After i.m. injection nicomorphine is relatively slowly absorbed from the muscular depot and is found in the serum for approximately 1 h. The rate of absorption differs between patients and governs the overall pharmacokinetic profile of the compound. The relative AUCs were nicomorphine 18%, 6-nicotinoylmorphine 17%, and morphine 65%. Nicomorphine and 6-nicotinoylmorphine have significantly higher AUCs after i.m. injection than after i.v. injection, while the AUC of morphine and the total AUC show no difference between the two modes of administration.
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    Decreased and variable systemic availability of zidovudine in patients with AIDS if administered with a meal (1991)
    Springer
    European journal of clinical pharmacology 40 (1991), S. 305-308 
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    ISSN: 1432-1041
    Keywords: Zidovudine ; acquired immunodeficiency syndrome (AIDS) ; pharmacokinetics ; bioavailability ; food intake
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The systemic availability of oral zidovudine has been studied in 13 patients with the acquired immunodeficiency syndrome (AIDS) dosed either fasting or with breakfast. The mean peak plasma concentration and AUC of zidovudine were significantly 2.8- and 1.4-times higher in fasting patients than in those treated during meal. In both conditions the mean half-life was about 1.5 h and the period of plasma zidovudine concentrations 〉1 μmol · l−1 was 2 h (NS). It is concluded that if zidovudine is taken on an empty stomach, high peak plasma concentrations and decreased variation in pharmacological parameters may be expected. Whether or not this will influence toxicity and efficacy remains to be shown.
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    Absorption of theophylline from a new theophylline controlled-release capsule (1991)
    Springer
    European journal of clinical pharmacology 40 (1991), S. 319-320 
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    ISSN: 1432-1041
    Keywords: Theophylline ; controlled-release formulation ; absorption ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
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    Diuretic effect and disposition of furosemide in cystic fibrosis (1991)
    Springer
    European journal of clinical pharmacology 40 (1991), S. 333-341 
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    ISSN: 1432-1041
    Keywords: Furosemide ; cystic fibrosis ; pharmacokinetics ; diuretic effect ; baseline urine flow
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacodynamics and kinetics of single oral and intravenous doses of furosemide were studied in 9 patients (mean age 18.5 y) with cystic fibrosis. The diuretic effect of furosemide lasted for 6 h after oral administration and 2 h following intravenous injection of the drug. The patients with cystic fibrosis had a more pronounced diuretic response both to the oral and intravenous treatments than that reported in normals. Furosemide caused a marked decrease in urine pH for 5 h following the oral dose and between the 2nd and 3rd h after i.v. injection. The baseline nocturnal urine flow rate in 7 of the 9 patients given furosemide orally was increased by 30.6% compared to that reported in healthy subjects. The bioavailability of furosemide, its mean absorption rate and the mean plasma and urinary elimination half-lives both of the oral and the intravenous drug were similar to those reported in normal subjects. The patients with cystic fibrosis showed, however, about double normal mean total clearance after both the oral and i.v. treatments, and its renal clearance was almost half the plasma clearance. Nonrenal clearance was markedly increased in the patients, which agreed with a considerable decrease in the renal excretion of the drug. The mean apparent volume of distribution was also markedly increased compared to data in the literature. Oral furosemide resulted in a moderate increase in haematocrit and haemoglobin levels in 7 of 9 patients with cystic fibrosis and marked hypokalemia developed in 6 of the 9 patients 6 h after dosing. Pulmonary function tests performed at that time were changed in an inconsistent manner. The sweat test was significantly perturbed in those subjects, although the concentration of chloride in sweat did not fall below 60 mEq/l in any of the sweat samples tested.
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    The pharmacokinetics and pharmacodynamics of lisuride in healthy volunteers after intravenous, intramuscular, and subcutaneous injection (1991)
    Springer
    European journal of clinical pharmacology 40 (1991), S. 399-403 
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    ISSN: 1432-1041
    Keywords: Lisuride ; pharmacokinetics ; prolactin concentrations ; healthy volunteers ; adverse effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The plasma concentration of lisuride and prolactin have been measured in twelve healthy male volunteers after IV, IM or SC injection of 25 μg lisuride hydrogen maleate as an aqueous solution. After IV administration the plasma lisuride fell in two phases with half-lives of 14 min and 1.5 h. Total clearance was 13 ml·min−1·kg−1. After IM and SC injection the plasma concentrations peaked at 12 to 15 min and the profiles were similar to that found after IV administration. The systemic availabilities were 90% and 94%, respectively. Prolactin concentrations were reduced by a maximum of 60% relative to the normal circadian rhythm after all three routes of administration. The treatments were well tolerated, the only adverse reactions reported by some of the volunteers being mild, transient dizziness, tiredness, and nausea.
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    Disposition of oral quinine in acute falciparum malaria (1991)
    Springer
    European journal of clinical pharmacology 40 (1991), S. 49-52 
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    ISSN: 1432-1041
    Keywords: Quinine ; pharmacokinetics ; falciparum malaria
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Plasma quinine concentrations following oral quinine sulphate 10 mg salt/kg have been measured by HPLC in 15 adult Thai patients with uncomplicated falciparum malaria. In 10 of the same patients the study was repeated in convalescence. In acute malaria plasma concentrations were approximately 50% higher than in convalescence; the mean acute peak plasma quinine concentration was 8.4 mg·l−1 compared to 5.7 mg·l−1 in convalescence. There was considerable variation in the rate of drug absorption, particularly in acute malaria. The mean time to peak plasma concentration was 5.9 h in acute malaria and 3.2 h in convalescence. The apparent clearance of oral quinine (CL/f) during the illness was 1.51 ml·kg−1·min−1, which was significantly lower than in convalescence — 2.67 ml·kg−·min−1. Estimated free quinine clearance was also lower in the acute phase: 30.6 compared to 49.0 ml·kg−1·min−1 in convalescence. Mean (SD) plasma protein binding of quinine was 94.7% in acute malaria and 92.8% in convalescence. Binding was significantly correlated with the plasma concentration of α1 acid glycoprotein (r=0.5), which was significantly higher in the acute phase; 1.48 g·l−1 compared to 1.05 g·l−1 during convalescence. Oral quinine sulphate was well absorbed in uncomplicated falciparum malaria. High blood concentrations following the administration of oral quinine in acute malaria are probably related to increased plasma protein binding, lower apparent volume of distribution, and a reduction in its systemic clearance.
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    Lack of effect of omeprazole treatment on steady-state plasma levels of metoprolol (1991)
    Springer
    European journal of clinical pharmacology 40 (1991), S. 61-65 
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    ISSN: 1432-1041
    Keywords: Omeprazole ; substituted benzimidazole ; metoprolol ; interaction ; cytochrome P450 ; debrisoquine hydroxylase ; pharmacokinetics ; adverse effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In a randomised double-blind crossover study, seven healthy males were concomitantly given metoprolol 100 mg o. d. as a controlled release formulation, and omeprazole 40 mg o. d. or placebo, for 8 days. Plasma levels of the R- and S-enantiomers of metoprolol were determined on the 8th day of each treatment. The subjects were also characterised by their metabolic capacity to hydroxylate debrisoquine. Concomitant omeprazole treatment had no significant influence on the steady-state plasma levels of the two enantiomers of metoprolol. All subjects were characterised by extensive debrisoquine hydroxylation, i.e. extensive metoprolol metabolism. As metoprolol is metabolised to a great extent by debrisoquine hydroxylase (IID6), it is concluded that concomitant omeprazole treatment will probably have a negligible influence on the metabolism of the relatively large number of drugs mainly metabolised by this isoenzyme of the cytochrome P450 family.
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    Is there a need for more precise definitions of bioavailability? (1991)
    Springer
    European journal of clinical pharmacology 40 (1991), S. 123-126 
    Details
    ISSN: 1432-1041
    Keywords: bioavailability definition ; health authorities ; pharmacokinetics ; drug registration Participants: L. P. Balant (Geneva, Switzerland), L. Z. Benet (San Francisco, USA), H. Blume (Eschborn, FRG), G. Bozler (Biberach, FRG), D. D. Breimer (Leiden, The Netherlands), M. Eichelbaum (Stuttgart, FRG), U. Gundert-Remy (Berlin, FRG), J. L. Hirtz (Paris, France), E. Mutschler (Frankfurt, FRG), K. K. Midha (Saskatoon, Canada), A. G. Rauws (Bilthoven, The Netherlands), W. A. Ritschel (Cincinnati, USA), L. N. Sansom (Adelaide, Australia), J. P. Skelly (Rockville, USA), and K.-O. Vollmer (Freiburg, FRG)
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary After evaluation of the present definitions in a set of particular cases, it was agreed that there was no need for “more precise” definitions and that the current ones were adequate in the majority of cases. However, it was felt that the present definitions might be improved, in particular in view of the existence of non-systemically acting drugs and future “targeted drugs”. Thus, the FDA definition might be modified as follows: “Bioavailability means the rate and extent to which the active drug ingredient or therapeutic moiety from a drug product becomes available at the site of drug action or in a biological medium believed to reflect accessibility to a site of action”.
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    Changes in gentamicin pharmacokinetic profiles induced by mechanical ventilation (1991)
    Springer
    European journal of clinical pharmacology 40 (1991), S. 297-302 
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    ISSN: 1432-1041
    Keywords: Gentamicin ; pharmacokinetics ; mechanical ventilation ; therapeutic dose range
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The influence of controlled mechanical ventilation (CMV) on the pharmacokinetic profile of gentamicin has been examined in 23 patients after elective open heart surgery. A parallel design was adopted in two groups of patients: 13 patients requiring CMV for at least 32 h after surgery, all of whom were able to breath spontaneously (SB) after 72 h (study group), and 10 patients who required CMV for only a brief period and who showed SB at 32 h postsurgery. Haemodynamic parameters remained stable throughout the study. Apparent volume of distribution (Vz), half-life (t1/2), total clearance (CL), peak (C max ss ) and trough (C min ss ) plasma levels at steady-state for target levels (6–8 μg/ml), were measured. In the study group significant differences between CMV and SB conditions were found in Vz (mean 0.36 and 0.25 l/kg), t1/2 (mean 3.63 and 2.90 h) and C max ss (mean 4.30 and 5.53 μg/ml) while C min ss (mean 1.06 μg·ml−1 and 0.92 μg·ml−1) did not change significantly. In contrast, the pharmacokinetics in the control group showed no differences. It appears that CMV leads to an increase in gentamicin Vz, which accounts for the fall in C max ss below the therapeutic dose range (〈5 μg/ml) recommended for gentamicin. It seems advisable to use a larger dose of gentamicin in patients receiving CMV, even before the level is assessed.
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    Pharmacokinetics of intravenous and oral chlordesmethyldiazepam in patients on regular haemodialysis (1991)
    Springer
    European journal of clinical pharmacology 41 (1991), S. 65-68 
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    ISSN: 1432-1041
    Keywords: Chlordesmethyldiazepam ; pharmacokinetics ; i.v./p.o. administration ; renal failure ; protein binding ; pharmacodynamics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of a single 2 mg IV dose of chlordesmethyldiazepam has been studied in 11 patients with renal failure on regular haemodialysis and in 11 age-matched healthy controls. The kinetics was also examined after a single 2 mg oral dose in 6 of the 11 renal failure patients. After intravenous administration the kinetics of total chlordesmethyldiazepam in renal patients and controls were the same. The unbound fraction of the drug in renal patients was higher (5.5%) than in controls (2.9%). Correction for differences in protein binding revealed a reduced apparent volume of distribution (47 vs. 140 l · kg−1) and a reduced clearance (5.0 vs. 10.5 ml · min−1 · kg−1) in the patients. The systemic availability of oral chlordesmethyldiazepam was good (82%) despite a relatively slow absorption rate.
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  • 59
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    Response to furosemide during dehydration with and without naproxen pretreatment of kidney donors and renal transplant recipients (1991)
    Springer
    European journal of clinical pharmacology 40 (1991), S. 209-214 
    Details
    ISSN: 1432-1041
    Keywords: Furosemide ; renal transplant recipients ; kidney donors ; naproxen ; dehydration ; pharmacokinetics ; salt-regulation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The response to 40 mg furosemide p.o. in 6 healthy kidney donors and 6 renal transplant recipients with and without naproxen pretreatment has been studied. No volume replacement was given in order to study the development of tolerance. The subjects showed an average dehydration of 1.5 kg · 6 h−1. While mean creatinine clearance was equal in patients and donors (76 vs 80 ml/min), renal furosemide clearance was significantly lower in the patients (47 vs 81 ml/min; P〈0.05). The patients also excreted a smaller fraction of the dose in the urine (5.7 vs 7.8 mg/6 h; P〈0.05). As the overall renal sensitivity was similar in the two groups, the natriuretic response was correspondingly smaller in transplant recipients as compared to donors. Within the observation period of 6 h after dosing, acute tolerance developed in the donors and in 4 of the 6 patients, as shown by clockwise hysteresis in the dose (urine furosemide excretion rate)-response (natriuresis) curves. Pretreatment with naproxen reduced renal sensitivity to furosemide (right shift of the dose response curve) in all the donors but in only 2 of the patients. In both groups acute tolerance was less pronounced after naproxen, which may indicate involvement of the prostaglandin system in the development of acute tolerance. The results may also indicate regeneration of sympathetic nerves with functional capacity in at least some renal transplants, or that other mechanisms of salt regulation compensate for loss of sympathetic nerve activity.
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    Monitoring of the free concentration of cyclosporine in plasma in man (1991)
    Springer
    European journal of clinical pharmacology 40 (1991), S. 571-575 
    Details
    ISSN: 1432-1041
    Keywords: Cyclosporine ; free drug in plasma ; therapeutic drug monitoring ; renal transplantation ; plasma binding ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The free fraction of cyclosporine A (CsA) and its total plasma concentration as determined by HPLC(CsAT) were prospectively monitored in 66 recipients of renal transplants. The free CsA levels (CsAu) were calculated. The variability in free CsA levels was no less than for total CsAT levels. The correlation between CsAu and CsAT was high (r=0.90). Both CsAT and CsAu covaried with serum triglycerides and apolipoprotein A1. Fourty-four of the 66 patients suffered acute rejection episodes on 69 occasions. CsAT and CSAu both decreased and to a similar extent at the occurrence of acute rejection (42% and 59% decrease, respectively; significant vs baseline. Notsignificant difference in decrease in CsATvsCsAu). Acute nephrotoxicity occurred on 11 occasions in 10 patients. Both CsAT and CSAu were approximately twice as high at the time of acute nephrotoxicity as compared to one week previously. Both CsAT and CsAu were higher during the first month after transplantation in patients with than in patients without systemic infection. Thus, plasma CsAu gave no additional clinical information or guidance compared to CsAT in renal transplant recipients. Due to the complexity of its assay, which requires two consecutive analyses, there does not appear to be any need for routine monitoring of CsAu in renal transplant recipients.
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    Flecainide: evidence of non-linear kinetics (1991)
    Springer
    European journal of clinical pharmacology 41 (1991), S. 57-59 
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    ISSN: 1432-1041
    Keywords: Flecainide ; pharmacokinetics ; ventricular arrhythmias
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of flecainide has been studied in 12 patients with ventricular arrhythmias, both after single administration and during chronic treatment. Both the half-life and the AUC were significantly increased during chronic treatment. This suggests that the kinetics of flecainide might be non-linear also in patients with normal kidney and liver function. The increase in plasma flecainide levels during chronic treatment could not be predicted, so close monitoring of its plasma levels is advisable.
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    Pharmacokinetic profile and tolerability of pimobendan in patients with terminal renal insufficiency (1991)
    Springer
    European journal of clinical pharmacology 40 (1991), S. 107-111 
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    ISSN: 1432-1041
    Keywords: Pimobendan ; pharmacokinetics ; tolerability ; renal impairment ; adverse effects ; haemodynamic actions
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of an i.v. bolus of pimobendan (P) 2.5 mg and 5.0 mg, its tolerability and the effect on heart rate and blood pressure have been studied in 12 subjects (42–70 y) suffering from severe terminal renal impairment. Plasma level data were compared with those obtained in a previous investigation in healthy volunteers. Pharmacokinetics were dose linear and were comparable to those in healthy subjects. No adjustment of the dose of P is necessary in patients with severe renal impairment. Tolerability of P, observed by means of blood pressure monitoring, clinical chemistry tests, electrocardiography and subjective judgement resulted in 4 complaints out of 12 patients: three suffered from orthostatic problems and vomiting, and one patient had nausea. Mean heart rate was elevated by 19% (2.5 mg) and 16% (5.0 mg). Blood pressure was significantly reduced after 2.5 mg P (23% systolic and 26% diastolic pressure), and after 5.0 mg P by 25% systolic and 23% diastolic pressure.
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    Clinical pharmacokinetics of 3-day continuous infusion cisplatin and daily bolus 5-Fluorouracil (1991)
    Springer
    European journal of clinical pharmacology 40 (1991), S. 115-117 
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    ISSN: 1432-1041
    Keywords: Cisplatin ; 5-Fluorouracil ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
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    URL: http://dx.doi.org/10.1007/BF00315150
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    Continuous infusion of high-dose metoclopramide: comparison of pharmacokinetically adjusted and standard doses for the control of cisplatin-induced acute emesis (1991)
    Springer
    European journal of clinical pharmacology 40 (1991), S. 283-286 
    Details
    ISSN: 1432-1041
    Keywords: Metoclopramide cancer chemotherapy ; emesis ; continuous infusion ; pharmacokinetics ; cisplatin ; adverse effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Metoclopramide was administered by continuous infusion to two groups each of 14 patients on chemotherapy, randomized to receive either doses adjusted to individual pharmacokinetic parameters or doses adjusted as usual to body weight. The mean plasma concentration at the end of the infusion in the adjusted group was 1.01 mg · 1−1, close to that aimed for (1.20 mg · 1−1). It was significantly different from that in the other group, v0.54 mg · 1−1. Antiemetic efficacy, defined as ⩽2 emetic events in the 24 h following cisplatin, was similar in both groups (being found in 12/14 (86%) and 10/14 patients (71%), respectively). Analysis of the cumulative percentage of responders according to plasma concentration showed a clear plasma concentration-effect relationship. Routine MCP pharmacokinetic dosage adjustment is not indicated, but this therapeutic approach can be used to optimize antiemetic therapy in poor responder patients.
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    Cyclosporine pharmacokinetics in liver transplant recipients: evaluation of results using both polyclonal radioimmunoassay and liquid chromatographic analysis (1991)
    Springer
    European journal of clinical pharmacology 40 (1991), S. 513-519 
    Details
    ISSN: 1432-1041
    Keywords: Cyclosporine ; liver transplant recipients ; radioimmunoassay ; pharmacokinetics ; bioavailability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Pharmacokinetic variables were derived from cyclosporine measurements using liquid chromatography (HPLC) and radioimmunoassay with a non-selective polyclonal antibody (PARIA) in 11 orthotopic liver transplant recipients studied in paired oral and intravenous studies both before and after permanent clamping of the biliary T-tube. After oral drug administration, mean areas under blood cyclosporine concentration versus time curves before clamping were around 5.2-fold greater by PARIA than HPLC but 2.9-fold greater after clamping and closer to comparable values after intravenous cyclosporine (2.5 and 2.3-fold, respectively). Cyclosporine clearance was smaller by PARIA than HPLC (mean 7.3 versus 3.3 ml · min−1 · kg−1, respectively, before clamping). Both values decreased by 25% after clamping (to 5.5 and 2.4 ml · min−1 · kg−1, respectively), although there was no significant change in distribution or elimination half-lives (around 0.5 and 8 h, respectively). The mean bioavailability of oral cyclosporine increased significantly after clamping in 9 patients (from 10.6% to 28.1% by HPLC and from 14.8 to 35.1% by PARIA) but in two patients who developed the vanishing bile duct syndrome values fell to 〈 10% and the proportional overestimation of cyclosporine concentrations by PARIA increased. Clamping had no significant effect on the mean apparent volumes of distribution but values of Vz were approximately twice those of Vss (around 2.6 and 1.3 l · kg−1 by PARIA and HPLC respectively). Mean half lives after clamping were shorter following oral than intravenous cyclosporine (t1/2λ2 around 15 h enterally versus 8 h parenterally). These data suggest delays in cyclosporine absorption and significant first pass metabolism which may contribute to higher PARIA:HPLC ratios after oral dosing and to reduced bioavailability before clamping.
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    Single-dose and steady-state kinetics of morphine and its metabolites in cancer patients — a comparison of two oral formulations (1991)
    Springer
    European journal of clinical pharmacology 40 (1991), S. 585-591 
    Details
    ISSN: 1432-1041
    Keywords: Morphine ; metabolites ; clinical trial ; pharmacokinetics ; controlled release formulation ; cancer patients ; adverse effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The single-dose and steady state kinetics of morphine given as controlled-release tablets (30 mg every 12 h) and as a solution (15 mg every 6 h) have been compared in 11 cancer patients with chronic pain. The concentrations of morphine, morphine-3-glucuronide (M3G), and morphine-6-glucuronide (M6G) were analyzed by HPLC. There were no significant differences between the tablets and solution in the mean steady state concentrations of morphine, M3G or M6G. The tmax was 3.3 h for the tablets compared to 1.1 h for the solution. After giving the controlled-release tablets every 12 h there was a significantly higher fluctuation index of the morphine concentrations than after the solution. Urinary recovery at steady state was comparable between the two preparations, with averages of 57% and 47%, respectively. Thus, no major differences were found in the pharmacokinetics of morphine and its glucuronidated metabolites after 30 mg morphine as controlled-release tablets every 12 h or 15 mg of morphine solution every 6 h, except for a significantly longer tmax and greater fluctuation in morphine concentrations after the controlled-release tablets.
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    Sublingual captopril — a pharmacokinetic and pharmacodynamic evaluation (1991)
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    European journal of clinical pharmacology 40 (1991), S. 393-398 
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    ISSN: 1432-1041
    Keywords: Captopril ; sublingual ; pharmacokinetics ; pharmacodynamics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In this study we compared the pharmacokinetics and pharmacodynamics of captopril after sublingual and peroral administration. Single 25 mg doses of captopril were administered sublingually and perorally on two different occasions in a randomised cross-over fashion to eight healthy volunteers aged 22–35 years. The kinetics of unchanged captopril, plasma renin activity (PRA), BP and heart rate were studied over three hours after both peroral and sublingual administration of captopril. Mean pharmacokinetic parameters for unchanged captopril after sublingual administration were: Cmax, 234 ng·ml−1; tmax, 45 min; AUC (0–3 h), 15.1 μg·ml−1. min. Mean pharmacokinetic parameters for unchanged captopril after peroral administration were: Cmax, 228 ng·ml−1; tmax, 75 min; AUC (0–3 h), 17.0 μg·ml−1. min. tmax was significantly shorter when captopril was administered sublingually; all other pharmacokinetic parameters were equivalent. The plasma captopril concentrations achieved post drug administration led to increases in PRA and reductions in BP. tmax for PRA was 86 min for sublingual captopril and 113 min for perorally administered drug. Peak PRA values were, however, not significantly different. BP, as expected, was not reduced dramatically in these healthy volunteer subjects, however, in systolic BP vs time profiles, BP was significantly lower after volunteers received sublingual captopril. Heart rate increased slightly after captopril administration; there were no differences between the two routes of administration. Administration of captopril sublingually, therefore led to a more rapid attainment of plasma captopril concentrations and had a more rapid onset of pharmacological effect when compared with peroral administration.
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    Pharmacokinetics of SUN 1165, a new antiarrhythmic agent, in renal dysfunction (1991)
    Springer
    European journal of clinical pharmacology 40 (1991), S. 411-414 
    Details
    ISSN: 1432-1041
    Keywords: SUN 1165 ; renal failure ; antiarrhythmic agent ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of a new Class I antiarrhythmic agent, SUN 1165, has been studied in 32 patients with varying degrees of renal impairment following a single oral dose of 50 mg. The apparent volume of distribution at steady state was 1.48 1 · kg−1, the absorption rate constant was 2.2 h−1, and plasma protein binding was 26.8% in subjects with normal renal function. These variables were not altered with renal impairment. More than 60% of SUN 1165 given orally was excreted unchanged via the kidney, both by tubular secretion and glomerular filtration. The elimination rate constant, the apparent total body clearance and the apparent renal clearance were linearly correlated with the endogenous creatinine clearance. The half-time of elimination was 3.4 h in normal subjects and it was prolonged to 23.7 h in severe renal failure (creatinine clearance below 20 ml · min−1 · 1.48 m−2). Dosage adjustment of SUN 1165 is necessary in renal failure.
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    Analysis of stable two-dimensional patterns in contractile cytogel (1991)
    Springer
    Journal of nonlinear science 1 (1991), S. 289-311 
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    ISSN: 1432-1467
    Keywords: cytogel ; mechanochemical ; two-dimensional patterns ; cellular differentiation ; pattern formation ; stability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Mathematics , Physics
    Notes: Summary Contractile actomyosin systems play a central role in the generation of intracellular patterns. Models for pattern formation have benefited greatly from the application of mechanochemical theory. However, investigations of the patterns have been primarily qualitative in nature; the two-dimensional nature of the evolving patterns has not yet been addressed mathematically, nor has the evolution of stable heterogeneous steady-state solutions. We consider these issues, supporting our analytical predictions with numerical simulations in one and two spatial dimensions. We show how, for certain gels, the two and three-dimensional tensor equation which describes a balance of forces can be reduced to a reaction-diffusion equation.
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    Characterization of members of a pseudogene subfamily of the wheat α-gliadin storage protein genes (1991)
    Springer
    Plant molecular biology 16 (1991), S. 335-337 
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    ISSN: 1573-5028
    Keywords: Triticum ; wheat ; endosperm ; gliadin ; pseudogene ; duplication ; evolution
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
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    Wheat ubiquitin gene exhibits a conserved protein coding region and a diverged 3′ non-coding region (1991)
    Springer
    Plant molecular biology 16 (1991), S. 907-908 
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    ISSN: 1573-5028
    Keywords: ubiquitin ; wheat ; heat shock protein
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
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    Site-directed mutagenesis and expression inEscherichia coli of WMAI-1, a wheat monomeric inhibitor of insect α-amylase (1991)
    Springer
    Plant molecular biology 17 (1991), S. 1005-1011 
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    ISSN: 1573-5028
    Keywords: α-amylase inhibitor ; expression inE. coli ; glycosylation versus activity ; insect α-amylase ; mutagenesis ; wheat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract The wheat monomeric inhibitor WMAI-1 (syn. 0.28) produced inEscherichia coli using the pT7-7 expression ventor has the correct N-terminal sequence and the same electrophoretic mobility and specific activity towards the α-amylase from the insectTenebrio molitor as the native WMAI-1 isolated from wheat. This confirms that the native inhibitor is not glycosylated and contradicts claims that a putative glycosyl moiety was essential for inhibition. Thirteen mutants have been obtained at six different sites. Substitution of the highly conserved N-terminal S by the sequence ARIRAR increased the pre-incubation time required for maximum activity. A similar result was obtained by insertion of GPRLPW after position 4, while insertion of EPRAPW at the same position rendered the inhibitor inactive. The substitution D/EGPRL and insertions DGP or D, at position 58, produced complete inactivation. All other mutations had only minor effects on activity.
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    A Triticum aestivum cDNA clone encoding a low-molecular-weight heat shock protein (1991)
    Springer
    Plant molecular biology 17 (1991), S. 273-275 
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    ISSN: 1573-5028
    Keywords: Tahsp17.3 ; low-molecular-weight HSP ; Triticum aestivum L. ; wheat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
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    Cloning and sequencing of cDNAs encoding a pathogen-induced putative peroxidase of wheat (Triticum aestivum L.) (1991)
    Springer
    Plant molecular biology 16 (1991), S. 329-331 
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    ISSN: 1573-5028
    Keywords: pathogen-induced ; peroxidase ; wheat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract We report here the complete amino acid sequence of a pathogen-induced putative peroxidase from wheat (Triticum aestivum L.) as deduced from cDNA clones representing mRNA from leaves infected with the powdery mildew fungus Erysiphe graminis. The protein consists of 312 amino acids, of which the first 22 form a putative signal sequence, and has a calculated pI of 5.7. Sequence comparison revealed that the putative wheat peroxidase is most similar to the turnip (Brassica rapa) peroxidase, with which it shares 57% identical and 13% conserved amino acids.
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    Sequence and tissue-specific expression of a putative peroxidase gene from wheat (Triticum aestivum L.) (1991)
    Springer
    Plant molecular biology 16 (1991), S. 171-174 
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    ISSN: 1573-5028
    Keywords: peroxidase gene ; wheat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract We have used a cDNA clone encoding a pathogen-induced putative wheat peroxidase to screen a genomic libary of wheat (Triticum aestivum L. cv. Cheyenne) and isolated one positive clone, lambda POX1. Sequence analysis revealed that this clone contains a gene encoding a putative peroxidase with a calculated pI of 8.1 which exhibits 58% and 83% sequence identity to the amino acid sequence of the turnip (Brassica rapa) peroxidase and a pathogen-induced putative wheat peroxidase, respectively. The two introns in the wheat gene are at the same positions as introns in the peroxidase genes of tomato and horseradish. Results of S1-mapping experiments suggest that this gene is neither pathogen-nor wound-induced in leaves but is constitutively expressed in roots.
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    Sequence analysis of a cDNA encoding a Group 3 LEA mRNA inducible by ABA or dehydration stress in wheat (1991)
    Springer
    Plant molecular biology 16 (1991), S. 1073-1076 
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    ISSN: 1573-5028
    Keywords: abscisic acid ; dehydration ; LEA ; water stress ; wheat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract A cDNA clone (pMA2005) of a Group 3 LEA (late embryogenesis abundant) protein has been sequenced from wheat. The wheat cDNA clone codes for a protein with ten tandem repeats of an 11 amino acid sequence and has homology to other Group 3 LEAs reported in barley, carrot, cotton and rape (L. Dure et al., Plant Mol Biol 12: 475–486, 1989). The deduced amino acid sequence indicates that the wheat protein has a molecular weight of 23 000 and is a basic, hydrophilic protein. Northern analysis with the cDNA clone shows that dehydration of wheat shoot tissue results in increased transcript levels that correlate with increases in endogenous ABA.
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    A novel proline-rich protein from wheat (1991)
    Springer
    Plant molecular biology 16 (1991), S. 663-670 
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    ISSN: 1573-5028
    Keywords: gene expression ; proline-rich protein ; wheat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract A cDNA (WPRP1) encoding a wheat proline-rich protein has been isolated and sequenced. The amino acid composition shows 45% proline, with high levels of methionine, lysine and glutamic acid. The derived 378 residue amino acid sequence has a highly repetitive structure which is unlike those of other proline-rich proteins. The WPRP1 cDNA clone was used to determine the copy number and chromosomal location of the WPRP1 gene by restriction fragment length polymorphism analysis of wheat inbred lines. Although WPRP1 is encoded by a single-copy gene it is also a representative of a larger family of related sequences. RNA gel blot analysis showed that expression of WPRP1 is highest in rapidly growing tissue which together with its amino acid composition suggests a structural role for the encoded protein.
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    A wheat glutathione-S-transferase gene with transposon-like sequences in the promoter region (1991)
    Springer
    Plant molecular biology 16 (1991), S. 1089-1091 
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    ISSN: 1573-5028
    Keywords: wheat ; glutathione-S-transferase ; transposon-like sequence
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
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    URL: http://dx.doi.org/10.1007/BF00016083
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    Nucleotide sequence of a wheat (Triticum aestivum L.) cDNA clone encoding the waxy protein (1991)
    Springer
    Plant molecular biology 16 (1991), S. 1099-1101 
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    ISSN: 1573-5028
    Keywords: wheat ; Triticum aestivum ; cDNA clone ; waxy protein
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
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    URL: http://dx.doi.org/10.1007/BF00016086
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    Structure and sequence of a wheat phosphoribulokinase gene (1991)
    Springer
    Plant molecular biology 17 (1991), S. 167-168 
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    ISSN: 1573-5028
    Keywords: chloroplast ; monocot gene ; phosphoribulokinase ; wheat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
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    URL: http://dx.doi.org/10.1007/BF00036823
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    Nucleotide sequence of a Triticum aestivum cDNA clone which is homologous to the 26 kDa chloroplast-localized heat shock protein gene of maize (1991)
    Springer
    Plant molecular biology 17 (1991), S. 255-258 
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    ISSN: 1573-5028
    Keywords: Tahsp26.6 ; chloroplast-localized HSP ; Triticum aestivum L. ; wheat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
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    URL: http://dx.doi.org/10.1007/BF00039500
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    Stability analysis for two kinds of equations in two-species population dynamics (1991)
    Springer
    Applied mathematics and mechanics 12 (1991), S. 1017-1021 
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    ISSN: 1573-2754
    Keywords: predator ; prey ; patch ; population ; stability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Mechanical Engineering, Materials Science, Production Engineering, Mining and Metallurgy, Traffic Engineering, Precision Mechanics , Mathematics , Physics
    Notes: Abstract In this paper we study the stability for equilibrium points of equations in two-population dynamics. We discuss two predator-prey-patch models. Model 1 is described by a differential equation. Model 2 is described by an integral differential equation. We obtain the conditions for the stability of their equilibrium points. The results show that the overall population stability despite local extinction is realizable.
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    The theorem of the stability of linear nonautonomous systems under the frequently-acting perturbation and its application in the stability analysis of robot (1991)
    Springer
    Applied mathematics and mechanics 12 (1991), S. 1057-1063 
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    ISSN: 1573-2754
    Keywords: stability ; nonautonomous system ; frequently-acting perturbation ; state transition matrix ; robot
    Source: Springer Online Journal Archives 1860-2000
    Topics: Mechanical Engineering, Materials Science, Production Engineering, Mining and Metallurgy, Traffic Engineering, Precision Mechanics , Mathematics , Physics
    Notes: Abstract The necessary and sufficient condition of the stability of linear nonautonomous system under the frequently-acting perturbation has been given and proved on the basis of [1] and [2], and the theorem of the equivalence on the uniform and asymptotical stability in the sense of Liapunov and the stability under the frequently-acting perturbation of linear nonautonomous system has been given in this paper. Besides, the analysis of the dynamic stability of robot has been presented by applying the theorem in this paper, which is closer to reality.
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    The linear stability of plane Poiseuille flow under unsteady distortion (1991)
    Springer
    Applied mathematics and mechanics 12 (1991), S. 539-545 
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    ISSN: 1573-2754
    Keywords: fluid flow ; stability ; unsteady ; plane Poiseuille flow ; multiple scale method
    Source: Springer Online Journal Archives 1860-2000
    Topics: Mechanical Engineering, Materials Science, Production Engineering, Mining and Metallurgy, Traffic Engineering, Precision Mechanics , Mathematics , Physics
    Notes: Abstract This paper investigates the linear stability behaviour of plane Poiseuille flow under unsteady distortion by multiscale perturbation method and discusses further the problem proposed by paper [1]. The results show that in the initial period of disturbance development, the distortion profiles presented by paper [1] will make the disturbances grow up, thus augmenting the possibility of instability.
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    Remarks of some problems for rectangular thin plates with free edges on elastic foundations (1991)
    Springer
    Applied mathematics and mechanics 12 (1991), S. 415-420 
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    ISSN: 1573-2754
    Keywords: bending ; flexural function ; stability ; vibration ; critical force ; frequency
    Source: Springer Online Journal Archives 1860-2000
    Topics: Mechanical Engineering, Materials Science, Production Engineering, Mining and Metallurgy, Traffic Engineering, Precision Mechanics , Mathematics , Physics
    Notes: Abstract For the bending, stability and vibrations of rectangular thin plates with free edges on elastic foundations, in this paper we give a flexural function which exactly satisfies not only all the boundary conditions on free edges but also the conditions at free corner points. Applying energy variation principle, we give equations defining parameters in flexural function, stability equation, frequency equation, and general formulae of minimum critical force and minimum eigenfrequency as well.
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    Cyclopentenyl cytosine: Interspecies predictions based on rodent plasma and urine kinetics (1991)
    Springer
    Investigational new drugs 9 (1991), S. 9-17 
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    ISSN: 1573-0646
    Keywords: cyclopentenyl cytosine ; interspecies ; pharmacokinetics ; toxicity
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary A hybrid compartmental-physiological model for cyclopentenyl cytosine (CPE-C) is designed on the basis of early limited rodent pharmacokinetic data. Application of model independent pharmacokinetics and biochemical knowledge was first used to conceptualize such a model. The approach was to scale the physiological parameters of the model (compartmental clearances) and keep constant the anatomic parameters of the model (compartment volumes). Scaling of physiological mechanisms was based on body weight/surface area ratios. Using these principles, simulations with the model can reasonably anticipate the in vivo behavior of (CPE-C) in several species (mouse, rat, dog). The model is useful in understanding species differences in pharmacokinetic behavior of CPE-C.
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    Ifosfamide pharmacokinetics (1991)
    Springer
    Investigational new drugs 9 (1991), S. 305-311 
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    ISSN: 1573-0646
    Keywords: ifosfamide ; pharmacokinetics ; review
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract This review examines and details the pharmacokinetics of ifosfamide (a congener of cyclophosphamide) when administered by a number of commonly used chemotherapeutic regimes. The influence of route of administration, schedule of administration and dose on the pharmacokinetics of ifosfamide and its metabolites are discussed. Oral fractionated ifosfamide therapy, which causes an excessively high incidence of neurotoxicity, is similar to intravenous fractionated therapy in that it exhibits a time dependent increase in ifosfamide metabolic clearance. Five g/m2 ifosfamide given intravenously as a short (half hour) or long (24 hr) infusion does not exhibit dose dependent (zero-order) pharmacokinetics. In patients who develop ifosfamide/mesna associated CNS toxicity the pharmacokinetics of parent ifosfamide are not aberrant. This implies that ifosfamide metabolites are more likely to be responsible for the neurotoxicity rather than the parent drug. The development of simple and more specific analytical methodology, will allow further studies of the pharmacokinetics of the active ifosfamide metabolite(s). This may lead to further optimisation of the therapeutic index of ifosfamide treatment.
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    The stability on the solution of the initial value problem (1991)
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    Applied mathematics and mechanics 12 (1991), S. 1001-1008 
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    ISSN: 1573-2754
    Keywords: stability ; initial value problem ; differentiability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Mechanical Engineering, Materials Science, Production Engineering, Mining and Metallurgy, Traffic Engineering, Precision Mechanics , Mathematics , Physics
    Notes: Abstract In this paper, using the differentiability of the solution with respect to the initial value and the parameter, we present a method which, different from Liapunov's direct method, will determine the stability of the non-stationary solution of the initial value problem when the non-stationary solution remains unknown.
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    The pharmacokinetics of aspirin in rats and the effect of buffer (1991)
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    Journal of pharmacokinetics and pharmacodynamics 19 (1991), S. 157-173 
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    ISSN: 1573-8744
    Keywords: aspirin ; rat ; pharmacokinetics ; effect of buffer
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Aspirin (acetylsalicyclic add) was administered to rats intravenously, orally, and intraintestinally at different doses or in different dosage forms. The distribution and elimination kinetics of aspirin in rats following intravenous administration were best described by a two-compartmental open system and were dose independent up to 15 mg/kg. The terminal elimination half-life following intravenous dosing (10 mg/kg) was 3.36±0.85min (n=15) with the clearance being 8.40±1.24 L/(kg.hr). Intravenous distribution and elimination kinetics of aspirin in rats were not influenced by an orally administered buffered solution with a buffer capacity of 0.933 mEq ANC (acid neutralizing capacity) per kg of body weight. However, this orally buffered solution did change the gastrointestinal absorption kinetics of aspirin in rats. The absolute bioavailable dose of aspirin was 56.6±10.4% (n=6)following its administration in an unbuffered solution while it was only 31.8±8.0% (n=6)following administration in the buffered solution. The corresponding values of the absolute bioavailable doses were 43.4±3.7% and 25.5±1.8% following intraintestinal administration. The lower systemic availability of aspirin in the presence of buffer is attributed to a greater fraction of the administered dose becoming available for absorption from the intestine where the extraction efficiency is higher than that in the stomach.
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    Pharmacokinetics and bioavailability of diclofenac in the rat (1991)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 19 (1991), S. 647-665 
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    ISSN: 1573-8744
    Keywords: diclofenac sodium ; biliary excretion ; pharmacokinetics ; bioavailability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Diclofenac sodium is a widely used drug with interesting absorption and disposition features when administered to laboratory animals. The present study was undertaken to assess the pharmacokinetics of the drug after iv and gastrointestinal dosing to rats. Renal excretion of unchanged drug was negligible, but biliary excretion of the drug (unchanged and conjugated) was detected in bile duct-cannulated rats; it accounted for 27.2 and 31.2% of the total dose following iv and intraduodenal administration, respectively. Most of the drug excreted in the bile was conjugated diclofenac; unchanged drug accounted for only 4.7 and 5.4% of total diclofenac excreted in the bile after iv and intraduodenal dosing, respectively. In normal animals, intestinal absorption of the drug excreted in the bile resulted in higher drug concentrations in plasma than those obtained in bile duct-cannulated rats, but only after 60 min of dosing. When administered directly into the duodenum, diclofenac absorption was extremely fast and the maximum plasma diclofenac concentration was reached within 2 min. After oral dosing, an early peak was also observed, but it was lower than that obtained after intraduodenal dosing: 71% diclofenac hioavailability was found in bile duct-cannulated rats intraduodenally dosed, whereas in normal animals dosed by mouth a bioavailability of 79% was obtained. In normal animals intraduodenally dosed, an apparent bioavailability of 106% was observed. All of these features, particularly the influence of enterohepatic circulation on drug bioavailability, are discussed.
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    Semiparametric analysis of non-steady-state pharmacodynamic data (1991)
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    Journal of pharmacokinetics and pharmacodynamics 19 (1991), S. 691-712 
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    ISSN: 1573-8744
    Keywords: pharmacokinetics ; pharmacodynamics ; linear system analysis ; nonlinear system analysis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract We present an approach to the analysis of pharmacodynamic (PD) data arising from non-steadystate experiments, meant to be used when only PD data, not pharmacokinetic (PK) data, are available. The approach allows estimation of the steady-state relationship between drug input and effect. The analysis is based on a model describing the time dependence of drug effect (E) on (unobserved) drug concentration (Ce) in an hypothetical effect compartment. The model consists of (i) a known model for the input rate of drug I(t), (ii) a parametric model; L(t, a) (a function of time t, and vector of parameters a), relating I to an observed variable X, (iii) a nonparametric model relating X to E. Ce is proportional to X. X(t) is given by I(X) * L(t, a)/AL, where L(t,α)=e −α 1 t * ∑ k=1 m , α2k e −α 2k+1 t, ∑ k=1 m α2k=1, AL=∫ 0 ∞ L(t) dt, and * indicates convolution.The nonparametric model relating X to Eis a cubic spline, a function of X and a vector of (linear) parameters β. The values of α and β are chosen to minimize the sum of squared residuals between predicted and observed E. We also describe a similar model, generalizing a previously described one, to analyze PK/PD data. Applications of the approach to different drug-effect relationships (verapamil-PR interval, hydroxazine-wheal and flare, flecainide and/or verapamil-PR, and left ventricular ejection fraction) are reported.
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    An approximate model-independent method to maintain constant plasma levels of intravenous drugs (1991)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 19 (1991), S. 635-645 
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    ISSN: 1573-8744
    Keywords: pharmacokinetics ; linear systems analysis ; statistical moments
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract To rapidly achieve and maintain constant plasma concentrations most intravenous drugs must be administered as an initial bolus followed by a combination of exponentially declining plus constantrate infusions. In the clinical practice of anesthesia and critical care medicine this is often not practical without specialized equipment. In this paper a simpler approach of maintaining approximately constant plasma concentrations is developed using a loading dose with a two- stage infusion scheme (an initial rapid infusion reduced at a given time to a lower rate). Equations are developed for determining the rate of the infusions as well as the duration of the initial infusion by equating moments of the Laplace transform of the approximate infusion to the moments of the Laplace transform of an exact solution. This approach is independent of models and uses as parameters the moments of the curve relating the concentration following a single iv dose of unit magnitude as a function of time. The accuracy of this technique was assessed by computer simulation.
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    Estimation of amobarbital plasma-effect site equilibration kinetics. Relevance of polyexponential conductance functions (1991)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 19 (1991), S. 617-634 
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    ISSN: 1573-8744
    Keywords: pharmacokinetics ; pharmacodynamics ; system approaches ; electroencephalogram ; amobarbital ; effect site equilibration
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The time delay between drug plasma concentrations and effect has been modeled most commonly by the effect compartment approach, assuming first-order monoexponential equilibrium kinetics between plasma and effect site. So far this assumption has not been rigorously probed. The purpose of the present investigation was to model the delay between amobarbital plasma concentrations and EEG effect using a new approach based on system analysis principles. This approach models the equilibrium between plasma and effect site without assuming a specific kinetic structure. Assuming linear distribution kinetics between plasma and effect site, the relationship between the two variables may be described by a convolution type of linear operation, involving a conductance function ϕ(t),which is approximated by a sum of exponentials. Six male Wistarderived rats received an iv infusion of amobarbital at a rate of 10mg/kg per min until isoelectric periods of 5sec or longer appeared on the EEG. Frequent arterial blood samples were obtained and EEG was continuously quantified using aperiodic analysis. The amplitudes in the 2.5–30Hz frequency band were used as EEG effect measure. The delay between plasma concentrations and EEG effect was best modeled by a biexponential conductance function. The use of a biexponential conductance function resulted in a significant further reduction (41 ± 10%)in hysteresis when compared to a monoexponential function, indicating that the assumption of simple first-order monoexponential equilibration kinetics is inadequate. The use of a biexponential conductance function also resulted in a significantly different shape of the effect site concenration- EEG effect relationship and hence the estimated pharmacodynamic parameters, when compared with a monoexponential function. This relationship showed a biphasic behavior, with EEG effects being maximal at amobarbital concentrations of 29.6± 1.3mg/L. At 80.2±2.0mg/L the EEG effect was reduced 50%below baseline values. A comparison was made with the equilibration between amobarbital plasma and cerebrospinal fluid (CSF) concentrations. Six male Wistarderived rats received an iv infusion of amobarbital, 10mg per min for 15min. Arterial blood and CSF samples were taken simultaneously at regular intervals. The equilibration between plasma and CSF concentrations was best fitted by a monoexponential conductance function. Significant differences in equilibration profiles of CSF and effect site with the plasma site were observed. To reach 50%equilibrium the effect site requires 2.5±0.3min and the CSF 3.5±0.2min, to reach 95%the values were, respectively, 90± 27and 15± 1min. This suggests that CSF is kinetically distinguishable from the effect site.
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    A pharmacokinetic model describing the removal of circulating radiolabeled antibody by extracorporeal immunoadsorption (1991)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 19 (1991), S. 385-403 
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    ISSN: 1573-8744
    Keywords: immunoadsorption ; pharmacokinetics ; extracorporeal ; monoclonal antibody ; compartmental model ; simulation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Extracorporeal immunoadsorption is a new technique for removal of circulating radiolabeled antibody from the peripheral blood (1) to reduce background activity for improved tumor imaging, and (2) to reduce whole-body and marrow toxicity when high doses of radiolabeled antibodies are used for antitumor therapy. A pharmacokinetic model was developed to describe plasma disappearance of111In -KC-4G3 prior to, during, and after immunoadsorption in humans. The model is developed based on a two-compartment open model, and during immunoadsorption a third compartment is added for removed radioactivity by the immunoadsorption column. Goodness-of-fit statistics indicate a good fit of the model to the data. The resulting pharmacokinetic parameters for a selected patient are V1=2.64L, Vss=3.64 L, t1/2α=3.77hr, and t1/2β hr. The immunoadsorption clearance (CL1A=19.3 ml/min) was 21-fold greater than the patient's plasma clearance (CL10=0.899 ml/min), indicating a very effective immunoadsorption process. The model predicts an increase in plasma radioactivity upon termination of immunoadsorption, probably due to redistribution of radioactivity from the extravascular compartment to the plasma in response to the rapid decline in plasma radioactivity during immunoadsorption. Two series of simulations were performed to examine the influence of onset time and duration of immunoadsorption. In series one the onset time was varied and in series two immunoadsorption duration was varied. In series one, the predicted radioactivity amounts adsorbed by the immunoadsorption column ranged from 75% of the injected dose (4-hr onset) to 52% of the injected dose (24-hr onset). In series two, immunoadsorbed radioactivity ranged from 32% (2-hr duration) to 64% of the injected dose (12-hr duration). When instituted as early as 4 hr, the predictions suggest that earlier immmoadsorption onset improves the effectiveness of radioactivity removal, relating to higher early circulation concentrations, and longer immunoadsorption periods remove more radioactivity, but also result in larger predicted radioactivity redistribution from tissue to plasma. To employ the immunoadsorption procedure for tumor imaging and therapy optimally, the data and our predictions indicate that a compromise must be made that will balance immunoadsorption onset and duration against tumor radioactivity uptake and subsequent radioactivity redistribution from tissues back to plasma. Together with biologic considerations providing sufficient antigenantibody interaction and dependent on the utilized radioisotope, these data support the utility of extracorporeal immunoadsorption during the radioimmunodetection of cancer and for future therapeutic applications.
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    A kinetic-dynamic model to explain the relationship between high potency and slow onset time for neuromuscular blocking drugs (1991)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 19 (1991), S. 537-552 
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    ISSN: 1573-8744
    Keywords: Modeling ; neuromuscular blocking drugs ; pharmacodynamics ; pharmacokinetics ; potency ; onset time
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract To account for experimental data showing increased onset time with increased potency of neuromuscular blocking drugs, a pharmacokinetic-pharmacodynamic model is presented. It is characterized by a finite concentration of receptors (R)in the effect compartment. Transfer from central to effect compartment is linearly related to concentration gradient. A sigmoid Emax model is used to describe the relationship between receptor occupancy and effect. Plasma concentrations found in the literature are used. Differential equations are solved numerically for equipotent doses of drugs of different potencies. Because the density of receptors constitutes a significant drain of drug molecules for potent drugs, the model predicts an inverse relationship between speed of onset and potency. The concentration of receptors in the effect compartment Rwhich best fits experimental data obtained in humans is 0.28 Μmol/L. With this value of R,onset times are prolonged when the ED95 (dose for 95% blockade) is less than 0.1 Μmol/kg. It is concluded that, in the development of a short-acting nondepolarizing neuromuscular blocking drug, agents having an ED95 of 0.1 Μmol/kg or greater appear more promising.
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    System analysis in multiple dose kinetics: Evidence for saturable tubular reabsorption of the organic cationN 1-methylnicotinamide in humans (1991)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 19 (1991), S. 553-574 
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    ISSN: 1573-8744
    Keywords: pharmacokinetics ; N 1-methylnicotmamide ; nicotinic acid metabolite ; organic cation ; saturation of tubular reabsorption ; tubular secretion ; system analysis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The renal clearance of N1-methylnicotinamide (NMN) was studied in 8 young women at physiological steady state and at steady state following a combined loading bolus and in infusion. Urinary NMN concentrations were determined using a new HPLC method, plasma levels by a conventional fluorescence method. At physiological levels net tubular secretion of NMN was evident due to a renal fractional excretion, i.e., a ratio of renal NMN clearance to creatinine clearance, above unity. Increasing plasma concentrations lead to an increase in the fractional excretion, indicating saturation of the underlying tubular reabsorption process. Binding to plasma proteins was excluded by ultra-filtration experiments. Clearances measured at physiological levels were about one half of the maximum renal clearance attained following the infusion. This maximum value was approximately six times the creatinine clearance and may be a useful approximation of the renal plasma flow. System analysis, including a novel method to calculate the net response following a multiple input, was used to determine the pharmacokinetic system parameters.
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    Role of bacterial cyanide production in differential reaction of plant cultivars to deleterious rhizosphere pseudomonads (1991)
    Springer
    Plant and soil 133 (1991), S. 93-100 
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    ISSN: 1573-5036
    Keywords: cultivars ; growth inhibition ; hydrogen cyanide ; lettuce ; Pseudomonas fluorescens ; volatile metabolites ; wheat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Agriculture, Forestry, Horticulture, Fishery, Domestic Science, Nutrition
    Notes: Abstract Lettuce and wheat cultivars, differing in reaction to root inoculation with plant growth-inhibitory bacteria, were tested for sensitivity to (i) gaseous metabolites produced by deleterious, cyanogenic isolates of Pseudomonas fluorescens, and to (ii) pure cyanide. Reactions were read as shoot and/or root elongation after exposure of seedlings to the volatiles in vitro. Lettuce cultivar Salad Bowl was significantly less sensitive than cv. Montana, both to bacterial volatiles and to pure cyanide, and a similar difference between these cultivars was also obtained in greenhouse experiments where bacteria were inoculated directly on the roots. Cultivar differences were, however, not recorded, either in vitro or in the greenhouse, when the bacteria were grown on a medium which did not support cyanide production. In wheat, a difference in sensitivity to bacteria-produced volatiles was recorded between two cultivars (Drabant and Besso) differing in reaction to bacterial inoculation, but in contrast to lettuce cultivars, the wheat cultivars tested did not react differentially to pure cyanide. The results suggest that in lettuce differential sensitivity to cyanide is one factor behind cultivar differences in reaction to the bacteria tested, even though bacterial metabolites other than cyanide may contribute to the plant growth inhibition recorded. In wheat, however, differential cultivar responses to these bacteria could not be shown to be related to cyanide.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00011903
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  • 98
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    Electronic Resource
    Variation for root traits and their genetic control in spring wheat (1991)
    Springer
    Euphytica 59 (1991), S. 1-8 
    Details
    ISSN: 1573-5060
    Keywords: Triticum aestivum ; wheat ; root ; combining ability ; correlation ; dry matter ; variation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Agriculture, Forestry, Horticulture, Fishery, Domestic Science, Nutrition
    Notes: Summary Wheat root characters which influence vital plant processes have scarcely been explored for their genetic control. This study was conducted to i) examine the diversity of root traits and associated shoot traits in spring wheat (Triticum aestivum L.) cultivars; ii) study the nature of genetic control of selected traits; and iii) examine associations among root and shoot traits. Three experiments were conducted in the greenhouse with plants grown in the vermiculite medium in clear plastic tubes. In the first experiment, 42 spring wheat cultivars were grown for three weeks and measurements were taken on root length, leaf length, root number, leaf number, root dry weight, and top dry weight. In the second study, 15F1's originating from a partial diallel mating of six cultivars along with the parents were evaluated for 4 weeks. The data on root length, leaf length, and root number were subjected to diallel analysis according to Griffing's method 4, fixed model. A third experiment consisted of studying 2 F2 populations with 141 plants per population. In the first study the 42 cultivars exhibited a wide range of variation for all six traits. Diallel analysis revealed significant effects of both general combining ability (GCA) and specific combining ability (SCA) for root length, leaf length, and root number. Parents with high GCA estimates were identified. Significant positive correlation coefficients were found among root and shoot traits. Analysis of F2's for root length indicated quantitative nature of inheritance of root length.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00025355
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  • 99
    Electronic Resource
    Electronic Resource
    Hybridization barriers between wheat and rye: In vitro pollen assays and electrophoretic survey (1991)
    Springer
    Euphytica 52 (1991), S. 147-153 
    Details
    ISSN: 1573-5060
    Keywords: Triticum aestivum ; wheat ; Secale cereale ; rye ; hybridization ; pollen-tube-growth ; wide-crosses
    Source: Springer Online Journal Archives 1860-2000
    Topics: Agriculture, Forestry, Horticulture, Fishery, Domestic Science, Nutrition
    Notes: Summary Five- to seven-day-old ovaries from Triticum aestivum vars Hope (non-crossable), Chinese Spring (CS, crossable) and the chromosomal substitution line Chinese Spring/Hope 5B (CS/H5B) were used to test the hypothesis that an ovarian substance inhibits rye (Secale cereale var Wrens) pollen tube growth. In vitro assays on a semi-solid medium demonstrated that a soluble, dialyzed lysate from Hope or CS/H5B ovaries inhibited rye pollen tube elongation significantly more than a similar lysate from CS ovaries (26%, 13% and 5% respectively compared to controls). When only the 20 longest tubes from each sample were included in the analysis the relationship was maintained (33%, 22% and 15% for Hope, CS/H5B and CS respectively). Heating the Hope lysate at 100° C for 10 min reduced the inhibition from 26% to 14% for all pollen tubes measured (n = 51 per sample) and from 33% to 20% when only the 20 longest pollen tubes per sample were analyzed. Isoelectric focusing followed by sodium dodecyl sulfate polyacrylamide electrophoresis (IEF/SDS-PAGE) and non-equilibrium pH gradient electrophoresis (NEPHGE) revealed several differences in the polypeptide profiles of soluble lysates from vars Hope, CS and CS/H5B. While two striking differences were observed, a 50 kilodalton (kD) polypeptide with an isoelectric point (pI) of approximately 8.5 and 100 kD polypeptide (pI∼4) from CS lysates which were considerably reduced in lysates of Hope and CS/H5B, none were obviously associated with the Hope 5B chromosome and therefore cross-incompatibility.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00029390
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  • 100
    Electronic Resource
    Electronic Resource
    Crossability of some bread wheat landraces and improved cultivars from western Himalayas with rye (1991)
    Springer
    Euphytica 53 (1991), S. 137-141 
    Details
    ISSN: 1573-5060
    Keywords: Triticum aestivum ; wheat ; Secale cereale ; rye ; crossability ; Himalayas
    Source: Springer Online Journal Archives 1860-2000
    Topics: Agriculture, Forestry, Horticulture, Fishery, Domestic Science, Nutrition
    Notes: Summary Crossability of 62 bread wheat accessions (14 landraces from Himachal Pradesh and 48 others) was examined with rye. The 3 rye cultivars did not differ in their relative crossability with 4 of the wheat accessions studied. On the other hand, the wheat cultivars differed greatly among themselves in their crossability with rye. Most of the wheat cultivars showed poor (〈10%) crossability. Two of the 14 landraces from Himachal Pradesh were found to be free from the crossability inhibitors as they showed very high (〉50%) crossability, whereas none of the other 48 cultivars studied was so.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00023794
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