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  • 1
    Electronic Resource
    Electronic Resource
    Dissociation between endothelium-mediated increases in tissue cGMP levels and modulation of aortic contractile responses (1984)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 328 (1984), S. 221-223 
    Details
    ISSN: 1432-1912
    Keywords: Endothelium ; cGMP ; Smooth muscle contraction ; Rat aorta
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Both methoxamine and clonidine elicited similar maximal contractions of rat isolated aorta in the absence of endothelium. These contractions were not associated with changes in tissue levels of cGMP or cAMP. In the presence of endothelium maximal methoxamine-induced contractions were not less than those elicited in the absence of endothelium but maximal clonidine-induced contractions were reduced to about 10% of those in the absence of endothelium. However, in the presence of endothelium both methoxamine and clonidine induced similar increases in tissue cGMP levels of about 1.5 to 2 fold; cAMP levels were unchanged. There is therefore a dissociation between endothelium-mediated inhibition of maximal contractile responses and increases in tissue levels of cGMP.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00512078
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    Paper (German National Licenses)
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  • 2
    Electronic Resource
    Electronic Resource
    Effect of endothelium on basal and α-adrenoceptor stimulated calcium fluxes in rat aorta (1986)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 334 (1986), S. 63-70 
    Details
    ISSN: 1432-1912
    Keywords: Vascular smooth muscle ; Endothelium ; 45Ca flux ; Rat aorta ; α-Adrenoceptor agonists
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The rate of unstimulated influx of Ca2+ into rat aorta smooth muscle, measured as uptake of 45Ca, was inhibited in the presence of endothelium as compared to influx in the absence of endothelium. Efflux of 45Ca from unstimulated prelabelled tissues was also reduced in the presence of endothelium. In normal physiological solution the rate of influx and efflux of Ca2+ stimulated by B-HT 920 (1 and 10 μM), but not that stimulated by phenylephrine (30 nM and 1 μM), was also reduced in the presence of endothelium. In the presence of the calcium entry blocker flunarizine (3 μM), phenylephrine (1 μM) stimulated efflux of Ca2+ was inhibited by the presence of endothelium. A correlation between inhibition of Ca2+ influx and modulation of α-adrenoceptor agonist-induced contractions by endothelium could not be demonstrated, and methylene blue, an antagonist of endothelium mediated inhibition of B-HT 920 contractions, did not affect Ca2+ influx stimulated by the agonist. The effects of endothelium on Ca2+ influx and efflux are unlikely to be due to alterations by endothelium of diffusion of 45Ca or the agonists in the vessel. The results demonstrate that an endothelial derived factor or factors can reduce calcium influx into smooth muscle cells and also modulate the release of calcium from cells, perhaps by affecting intracellular calcium pumping mechanisms. A reduction of calcium influx cannot be the sole explanation for the modulatory effect of endothelium on α-adrenoceptor agonist-induced contractions but an effect on intracellular calcium metabolism may be important.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00498741
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  • 3
    Electronic Resource
    Electronic Resource
    Effect of endothelium and carbachol on α-adrenoceptor agonist stimulated uptake and efflux of 45Ca in rat isolated aorta (1987)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 336 (1987), S. 287-294 
    Details
    ISSN: 1432-1912
    Keywords: Endothelium ; Calcium fluxes ; Alpha ; Adrenoceptor agonist ; Rat aorta ; Carbachol
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Preincubation with carbachol (10 μM) did not affect basal 45Ca accumulation by rat isolated aortic segments complete with endothelium, although 45Ca accumulation was enhanced by removal of endothelium. This confirms the observation that in the presence of endothelium Ca2+ influx in rat aorta is antagonized, and indicates that the basal release of an endothelial derived factor might be sufficient to maximally antagonize basal Ca2+ influx, or alternatively that EDRF released as a result of muscarinic stimulation does not have identical effects to the factor released under basal conditions. Accumulation of 45Ca stimulated by B-HT 920 but not that stimulated by phenylephrine was antagonized in the presence of endothelium. Contractions elicited by B-HT 920 were abolished in the presence of endothelium while contractions evoked by phenylephrine were reduced by about 50%. Preincubation with 10 μM carbachol antagonized both phenylephrine (1 μM) stimulated 45Ca accumulation and contractile responses in the presence of endothelium to about the same extent. Therefore, it might be concluded that the inhibitory effect of EDRF in this tissue is due to an inhibition of stimulated Ca2+ influx. However, while addition of carbachol to tissues precontracted with phenylephrine elicited an immediate relaxation in the presence of endothelium, this relaxation could not be correlated with a reduction in tissue accumulation of 45Ca. Carbachol also antagonized the phenylephrine-induced reduction of tissue 45Ca content (i.e. efflux of Ca2+), in tissues preloaded with 45Ca. This implies that the initial endothelial-mediated relaxant effect of carbachol in precontracted tissues cannot be explained either by reduced influx or by an enhanced efflux of Ca2+ from the smooth muscle cells. Therefore, it is concluded that although EDRF mediates a reduction in agonist-induced Cat2+ uptake it also exerts other effects, one of which may be an initial redistribution of intracelllar Ca2+, resulting in a reduction in free intracellular Ca2+ levels and therefore in relaxation.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00172680
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  • 4
    Electronic Resource
    Electronic Resource
    Determination of theophylline clearance in South African children (1993)
    Springer
    European journal of clinical pharmacology 44 (1993), S. 369-375 
    Details
    ISSN: 1432-1041
    Keywords: Theophylline ; children ; population pharmacokinetics ; Nonmem ; age ; gender ; race
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Theophylline clearance values in South African children were determined using 400 serum theophylline concentration measurements gathered from 109 compliant outpatients during their normal routine care. Population pharmacokinetic analysis was done using the Non-Linear Mixed Effects Model (Nonmem) to analyse the data. Nonmem was also used to estimate the influence of fixed effects (weight, age, race, gender etc) on clearance and its interindividual variability. Gender, age, and weight raised to an iterated exponent were found to be the most important demographic fixed effect parameters influencing clearance. Race was not found to be important. The weight-adjusted values of theophylline clearance decreased with increasing age. The actual values expressed in l·h−1·kg−1 were 0.0949 for children aged 1–5 y; 0.0813 for children aged 5–9 y, and 0.0660 for children of 9–16 y. The values are similar to those reported in other studies.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00316475
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    Paper (German National Licenses)
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  • 5
    Electronic Resource
    Electronic Resource
    Ketotifen pharmacokinetics in children with atopic perennial asthma (1997)
    Springer
    European journal of clinical pharmacology 52 (1997), S. 383-386 
    Details
    ISSN: 1432-1041
    Keywords: Key words Ketotifen; pharmacokinetics ; children ; ␣clearance
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: Published pharmacokinetic data on ketotifen are sparse, although it is a commonly used prophylactic agent in various allergic disorders in adults and children. The aim of this study was to assess the steady-state pharmacokinetics of ketotifen in children with atopic perennial asthma who were participating in a clinical trial. Method: The NONMEM population approach with sparse sampling was utilized. The data set consisted of 239 samples from 48 children who were randomized to receive either 1 mg or 2 mg oral ketotifen daily. Patients underwent a clinical examination and had a blood sample taken at 2-week intervals for 12 weeks. The ketotifen concentrations were measured by RIA. Results: A one-compartment model with first-order absorption was fit to the data. Volume was estimated at 394 l and clearance (CL) at 97.4 l · h−1 (3.6 l · h−1 · kg−1). Weight or body surface area were the most influential covariates for explaining interindividual variability in CL. The 2-mg dose appeared to have a relative bioavailability of 85% of the 1-mg dose. Conclusion: Children have a faster clearance of ketotifen than adults and would therefore require a higher dose per kilogram body weight to give comparable steady-state levels.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002280050305
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  • 6
    Electronic Resource
    Electronic Resource
    Determination of phenobarbitone population clearance values for South African children (1995)
    Springer
    European journal of clinical pharmacology 48 (1995), S. 381-383 
    Details
    ISSN: 1432-1041
    Keywords: Phenobarbitone ; children ; population pharmacokinetics ; NONMEM ; concomitant medication
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Non-linear Mixed Effects Modelling (NONMEM) was used to estimate phenobarbitone population clearance values for South African children, using 52 serum levels gathered from 32 patients during their routine care. NONMEM was also used to evaluate the influence of fixed effects such as weight, age and concomitant medication. The final model describing phenobarbitone clearance was CL=[Exp(0.0288 Wt−2.53)] M, where CL=clearance (l·h−1), Exp=the base of the natural logarithm, Wt=patient weight (kg) and M=a scaling factor for concomitant medication with a value of 1 for patients on phenobarbitone monotherapy, 0.62 for those receiving concomitant valproate and 0.87 for those patients receiving concomitant carbamazepine or phenytoin. Mean (95% confidence interval) phenobarbitone clearance values were 7.6 ml·h−1·kg−1 (6.2, 9.0 ml·h−1·kg−1) for the monotherapy group, 5.0 ml·h−1·kg−1 (4.0, 6.0 ml·h−1·kg−1) in the presence of concomitant valproate and 6.8 ml·h−1·kg−1 (5.6, 8.0 ml·h−1·kg−1) in the presence of concomitant carbamazepine or phenytoin. These values are similar to those previously reported from both traditional and NONMEM pharmacokinetic studies.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00194954
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