bluuebunny/crossref_metadata_2025_split huggingface dataset:
Bisoprolol attenuates noradrenaline‐ and phenylephrine‐evoked venoconstriction in man in vivo
Authors: Abdelmawla A. H. , Langley R. W. , Szabadi E. , Bradshaw C. M. 
Published: October 2003

Aims The aim of this study was to examine the effects of bisoprolol (BIS), a selective β1‐adrenoceptor antagonist without partial agonistic activity, on noradrenaline‐ and phenylephrine‐evoked venoconstriction in man using the dorsal hand vein compliance technique. Methods Twelve healthy male volunteers participated in three weekly experimental sessions. Subjects were allocated to treatments and sessions on a double‐blind basis. In each session either BIS 5 mg (BIS5), or BIS 10 mg (BIS10), or placebo was administered orally, and noradrenaline acid tartrate (0.1–33.33 ng min−1 ) followed by phenylephrine hydrochloride (0.033–10 μg min−1 ) was infused into the dorsal hand vein. Systolic and diastolic blood pressure and heart rate were also measured. Results Both noradrenaline and phenylephrine produced dose‐dependent venoconstriction: the geometric mean ED50 for noradrenaline was 3.21 ng min−1 and for phenylephrine 135.04 ng min−1; the potency ratio (noradrenaline/phenylephrine) was 42. Both BIS5 and BIS10 significantly decreased the venoconstriction to noradrenaline (ANOVA; P<0.005), and to phenylephrine (ANOVA; P<0.001). The antagonism of the venoconstrictor responses was also reflected in a significant increase in logED50 values for both noradrenaline (ANOVA; P<0.005), and phenylephrine (ANOVA; P<0.0025) in the presence of both doses of BIS. Both doses of BIS significantly decreased heart rate (ANOVA; P<0.0001), and systolic blood pressure (ANOVA; P<0.0025). Conclusions Bisoprolol can antagonize α1‐adrenoceptor mediated venoconstriction in the human dorsal hand vein in vivo through a mechanism which remains to be elucidated.
Erythropoietin production in healthy volunteers subjected to controlled hypobaric hypoxia: further evidence against a role for adenosine
Authors: Gleiter C. H. , Becker T. , Wenzel J. 
Published: October 2003

Aims Objective of this study was to investigate whether adenosine modulates renal erythropoietin production.Methods In the present study erythropoietin production was stimulated by hypobaric hypoxia by subjecting healthy volunteers to a simulated altitude of 4000 m in a low pressure chamber for 5.5 h. During exposure to hypoxia the subjects received i.v. in a randomized, single‐blind, cross‐over fashion the non‐specific adenosine antagonist theophylline, the adenosine reuptake inhibitor dipyridamole and placebo.Results Contrary to the working hypothesis, theophylline did not decrease and dipyridamole did not further boost erythropoietin concentrations.Conclusions The results are in agreement with our earlier study using haemorrhage as a controlled physiological stimulus of erythropoietin production, and would question a major role for adenosine as a mediator of renal erythropoietin production.
Inhibition of vasoconstriction by potassium channel opener aprikalim in human conduit arteries used as bypass grafts
Authors: He Guo‐Wei , Yang Cheng‐Qin 
Published: October 2003

Aims Potassium channel openers (KCOs) are of potential therapeutic value. Little is known about the effect of these drugs on human conduit arteries used as coronary bypass grafts. The purpose of this study was to determine the effect of the KCO aprikalim (RP52891) on human arteries used as coronary bypass grafts with emphasis on the possible difference in the inhibitory effect on depolarizing agent‐mediated rather than receptor‐mediated contraction. Methods Human internal mammary artery segments (IMA, n=88) taken from 28 patients were studied. Concentration‐relaxation curves for aprikalim were established in IMA precontracted with three vasoconstrictors (K+, U46619, and phenylephrine). In IMA rings incubated with aprikalim (1 or 30 &mgr;m ) for 10 min concentration‐contraction curves for the three vasoconstrictors were constructed. Results Aprikalim‐induced relaxation was less in K+ (37.3±6.4%) than in U46619 (80.2±7.7%, P=0.002), or phenylephrine (67.5±7.0%, P=0.038) ‐precontracted IMA. The EC50 for K+‐(−5.40±0.12 log m ) was significantly higher than that for phenylephrine (−6.43±0.30 log m, P=0.007) but not significant compared with that for U46619 (−5.81±0.11, P >0.05). Pretreatment with aprikalim depressed the contraction by phenylephrine from 140.6±27.6% to 49.3±14.1% (P=0.002) and shifted the EC50 11.0‐fold higher in rings treated with 1 &mgr;m aprikalim (P=0.007). Treatment of aprikalim did not significantly reduce the K+ and U46619‐induced contraction (P >0.05) but shifted the concentration‐contraction curves rightward (2.8‐fold higher for K+, P<0.05 and 2.2‐fold higher for U46619, P<0.05). Conclusions This study demonstrates that aprikalim has vasorelaxant effects in human conduit arteries used as coronary artery bypass grafts contracted by a variety of vasoconstrictors and this effect is vasoconstrictor‐selective with greater potency for &agr;1‐adrenoceptor agonists than for depolarizing agent K+. These findings provide information on the possible use of this KCO in various clinical settings.
Evening dosing is associated with higher plasma concentrations of pranlukast, a leukotriene receptor antagonist, in healthy male volunteers
Authors: Brocks Dion R. , Upward James , Davy Maria , Howland Kate , Compton Christopher , McHugh Charles , Dennis Michael J. 
Published: October 2003

Aims To study the magnitude of differences in the pharmacokinetics of pranlukast, after morning and evening administration. Methods Pranlukast (300 mg) was administered to 12 healthy male volunteers on two separate occasions, either in the morning or evening. Both doses were given 30 min after a standard high fat content meal. Blood samples were collected up to 18 h postdose. Plasma was assayed by high performance liquid chromatography. Standard pharmacokinetic and statistical analyses were performed. Results Statistically significant (P<0.05) increases were noted in AUC(o,t ) (56%) and tmax (2.5 h) after evening administration. Cmax was 14% higher after evening dosing (95% C.I. 0.71–1.84). Conclusions Pranlukast bioavailability is apparently increased after evening dosing as compared with morning administration. Higher night‐time and early morning plasma concentrations may confer additional therapeutic benefit at a time when asthmatics are at greatest risk of developing bronchospasm.
The risk of acute liver injury associated with cimetidine and other acid‐suppressing anti‐ulcer drugs
Authors: García Rodríguez Luis A. , Wallander Mari‐Ann , Stricker Bruno H. Ch. 
Published: October 2003

Aims The objective of this study was to estimate the risk of acute liver injury associated with individual acid‐suppressing drugs and assess the role of dose and duration of treatment. Methods We used a nested case‐control study design within a cohort of over 100 000 users of cimetidine, famotidine, omeprazole and ranitidine. The primary source of information was the General Practitioners Research Database. We identified 108 981 persons aged 20–74 years who received at least one prescription for cimetidine, famotidine, omeprazole, or ranitidine during 1990–93, and we ascertained the first occurrence of clinically acute liver injury referred to a specialist or admitted to a hospital. Results After review of medical records, 33 patients were considered eligible cases of idiopathic acute liver injury with no fatal cases. The type of liver injury was hepatocellular in almost half of the cases, and 80% of all cases presented with jaundice. Twelve cases occurred among current users of cimetidine, five among ranitidine users and one in an omeprazole user. The absolute risk of acute liver injury associated with cimetidine was estimated to be slightly greater than one per 5000 users of cimetidine. The adjusted relative risk (RRs) and 95% CI of developing acute liver injury associated with current use of cimetidine compared to non‐use was 5.5 (1.9–15.9), with omeprazole 2.1 (0.2–19.2) and with ranitidine 1.7 (0.5–5.8). In the absence of concomitant use of other hepatotoxic drugs, the RR with cimetidine was 14.4 (2.8–73.7). Among users of cimetidine, the risk was especially high in the first 2 months of starting therapy (RR: 11.3, 3.7–35.1) and at daily doses of 800 mg or greater (RR: 8.8, 3.0–26.0). Conclusions Cimetidine was the individual anti‐ulcer drug with the highest risk of developing symptomatic acute liver disease. Further data are required to confirm this finding. Our study indicates that there is a dose relationship and a short latent period between cimetidine treatment and acute liver injury.
1‐Methylxanthine derived from caffeine as a pharmacodynamic probe of oxypurinol effect
Authors: Birkett D. J. , Miners J. O. , Valente L. , Lillywhite K. J. , Day R. O. 
Published: October 2003

Aims In the present study we have investigated the use of caffeine, administered in the form of instant coffee, as a prodrug for 1MX to validate the use of the 1MU:1MX ratio following caffeine administration as a pharmacodynamic measure of oxypurinol effect on xanthine oxidase. Methods Five healthy volunteers took caffeine 75 mg 8 hourly administered as instant coffee over a 7 day period. They were given allopurinol 600 mg on day 4. Urine was collected in 8 h aliquots from day 1–day 7. The ratio of 1‐methyluric acid (1MU) to 1‐methylxanthuric (1MX) was determined. Results The relationship between the plasma oxypurinol (the active metabolite of allopurinol) concentration at the midpoint of each caffeine dosage interval and the decrement in the urinary 1MX to 1MU ratio fitted well by a sigmoid Emax model. Mean (±s.d.) values of the oxypurinol EC50(3.9±1.4 mg l− 1 ), EC90(8.7±1.8 mg l− 1 ) and the exponent, n (3.0±1.2) were similar to those obtained previously following either the direct administration of 1MX or the use of theophylline as a prodrug for 1MX. Conclusions These data indicate that the use of caffeine as a source of 1MX could provide a simple and ethically acceptable method for monitoring oxypurinol effect in patients taking allopurinol for the treatment of gout.
Influence of SNN‐6010, an elemental diet, on the generation of cytokines, NO, and chemiluminescence from leukocytes and umbilical vein endothelial cells in man
Authors: Ueta Eisaku , Yoneda Kazunori , Yamamoto Tetsuya , Osaki Tokio 
Published: October 2003

Aims There is insufficient information on the influence of elemental diet (ED) on leukocytes and endothelial cells although ED has been used increasingly for debilitated and post‐operative patients. We here aimed to show the influence of SNN‐6010 (Twinline®; TL), which contains medium‐chain triglycerides, on the generation of cytokines and nitric oxide (NO) and chemiluminescence in human umbilical vein endothelial cells (HUVEC) and leukocytes. Methods Leukocytes were obtained from 10 healthy volunteers and 10 patients with jaw fractures who underwent TL for 30 days after intermaxillary fixation. Luminol‐dependent chemiluminescence and NO generation were measured in polymorphonuclear leukocytes (PMN) and HUVEC and generation of interleukin‐1 beta (IL‐1&bgr;), tumour necrosis factor‐alpha (TNF‐&agr;), and prostaglandin E2 (PGE2 ) as well as expression of these cytokines’ mRNA were examined in lymphocytes, monocytes, PMN, and HUVEC. Results TL dose‐dependently suppressed generation of IL‐1&bgr;, TNF‐&agr;, PGE2, and NO in all kinds of cells from healthy individuals. Lymphocytes from patients who underwent TL feeding for 30 days showed reduced generation of IL‐1&bgr; and TNF‐&agr;, and the suppressed cytokine generation corresponded with the decreased expression of mRNA of these cytokines. Chemiluminescence by PMN from healthy individuals was suppressed by TL dose‐dependently, and PMN from TL‐fed patients showed reduced chemiluminescence. Conclusion These results appear to indicate that TL suppresses the functions of leukocytes and endothelial cells by down‐regulating the generation of reactive oxygen intermediates, NO, and cytokines.
Diltiazem‐cyclosporin pharmacokinetic interaction — dose–response relationship
Authors: Jones Terry E. , Morris Raymond G. , Mathew Timothy H. 
Published: October 2003

Aims To study the dose‐response relationship of the pharmacokinetic interaction between diltiazem and cyclosporin in kidney transplant recipients. Methods Eight stable kidney transplant recipients maintained on cyclosporin but not taking diltiazem, were given increasing doses of diltiazem to a maximum dose of 180 mg day−1. Following a 2 week period on each dose of diltiazem, thirteen blood samples were taken over a 24 h period to allow morning and evening AUCs to be determined for cyclosporin, diltiazem and three metabolites of diltiazem. Results Mean cyclosporin AUC(0, 24 h) increased sharply following the lowest dose of diltiazem used (10 mg day−1 ), the rate of increase slowed after 30–60 mg day−1 but continued to increase up to the maximum dose tested. The effect of a single morning dose of DTZ was evident over both morning (0–12 h) and evening (12–24 h) cyclosporin AUCs. There was considerable interpatient variation in response to DTZ. Conclusions The dose of diltiazem required to increase cyclosporin AUC (and hence allow significant reduction in cyclosporin dose) is less than that currently used for many patients. Lower doses of diltiazem should result in fewer adverse effects and may allow its use in situations where it was hitherto contraindicated. Because of the significant interpatient variation in response, we recommend individual patient blood cyclosporin concentration monitoring both before and after the introduction of diltiazem.
Characterization of the human cytochrome P450 enzymes involved in the metabolism of dihydrocodeine
Authors: Kirkwood L. C. , Nation R. L. , Somogyi A. A. 
Published: October 2003

Aims Using human liver microsomes from donors of the CYP2D6 poor and extensive metabolizer genotypes, the role of individual cytochromes P‐450 in the oxidative metabolism of dihydrocodeine was investigated. Methods The kinetics of formation of N‐ and O‐demethylated metabolites, nordihydrocodeine and dihydromorphine, were determined using microsomes from six extensive and one poor metabolizer and the effects of chemical inhibitors selective for individual P‐450 enzymes of the 1A, 2A, 2C, 2D, 2E and 3A families and of LKM1 (anti‐CYP2D6) antibodies were studied. Results Nordihydrocodeine was the major metabolite in both poor and extensive metabolizers. Kinetic constants for N‐demethylation derived from the single enzyme Michaelis‐Menten model did not differ between the two groups. Troleandomycin and erythromycin selectively inhibited N‐demethylation in both extensive and poor metabolizers. The CYP3A inducer, α‐naphthoflavone, increased N‐demethylation rates. The kinetics of formation of dihydromorphine in both groups were best described by a single enzyme Michaelis‐Menten model although inhibition studies in extensive metabolizers suggested involvement of two enzymes with similar Km values. The kinetic constants for O‐demethylation were significantly different in extensive and poor metabolizers. The extensive metabolizers had a mean intrinsic clearance to dihydromorphine more than ten times greater than the poor metabolizer. The CYP2D6 chemical inhibitors, quinidine and quinine, and LKM1 antibodies inhibited O‐demethylation in extensive metabolizers; no effect was observed in microsomes from a poor metabolizer. Conclusions CYP2D6 is the major enzyme mediating O‐demethylation of dihydrocodeine to dihydromorphine. In contrast, nordihydrocodeine formation is predominantly catalysed by CYP3A.
Benazepril, an angiotensin converting enzyme inhibitor: drug interaction with salbutamol and bronchial response to histamine in normal subjects
Authors: Bauer K. G. , Brunel P. , Nell G. , Quinn G. , Kaik G. A. 
Published: October 2003

Aims To investigate the effect of the angiotensin converting enzyme inhibitor, benazepril, on pulmonary function. Methods We investigated the influence of benazepril, on lung function and the interaction with inhaled salbutamol (0.1 to 6.6 mg) and histamine (0.03 to 30.69 g l−1 ) in normal subjects. Benazepril 20 mg, salbutamol 8 mg, propranolol 160 mg, and placebo were given orally once daily over 10 days. Results On day 8, there was no difference in the area under the salbutamol dose‐response curves between benazepril, placebo and oral salbutamol (P >0.05), propranolol shifted the curves to the right (P<0.05). On day 10, histamine challenge resulted in following PD35sGaw values (geometric mean and 95% CI): with placebo 1.02 (0.95–1.09) g l−1, benazepril 1.04 (0.99–1.08), salbutamol 1.19 (1.13–1.25), propranolol 0.57 (0.50–0.65). Conclusions Benazepril had no influence on baseline lung function, caused no interaction with inhaled salbutamol and the bronchial response to histamine was similar to placebo. However, our findings in normal subjects cannot be extrapolated automatically to asthmatics.
PMA‐induced megakaryocytic differentiation of HEL cells is accompanied by striking modifications of protein kinase C catalytic activity and isoform composition at the nuclear level
Authors: Zauli Giorgio , Bassini Alessandra , Catani Lucia , Gibellini Davide , Celeghini Claudio , Borgatti Paola , Caramelli Elisabetta , Guidotti Lia , Capitani Silvano 
Published: October 2003

We investigated whether members of the protein kinase C (PKC) family of enzymes could play a role in the nuclear events involved in megakaryocytic differentiation. PKC activity was analysed using a serine substituted specific peptide, which enabled us to evaluate the whole catalytic activity in the pluripotent haemopoietic HEL cell line treated with 10−7 m phorbol myristate acetate (PMA) or haemin. In parallel, the subcellular distribution of different PKC isoforms (α, βI, βII, γ, δ, ε, θ, η, ζ) was evaluated by Western blot. PKC catalytic activity in the nuclei of HEL cells showed a peak after acute (30 min) treatment with PMA, followed by a significant (P < 0.05) decline after prolonged exposure (72 h) to the same agonist, when most HEL cells had acquired a differentiated megakaryocytic phenotype. Western blot analysis of nuclear lysates consistently showed a significant increase of PKC‐α, ‐βI, ‐ε, ‐θ and ‐ζ isoforms after 30 min of PMA treatment, followed by a drastic decline of all but PKC‐ζ isoforms. Moreover, PKC‐δ appeared in HEL nuclei only after 72 h of exposure to PMA. On the other hand, neither the catalytic activity nor the immunoreactivity of the different PKC isoforms showed remarkable variations in nuclei of HEL cells induced to differentiate along the erythroid lineage with 10−7 m haemin.The possible implications of these findings for a better understanding of the molecular events underlying the process of megakaryocytic differentiation are discussed.
Continuing care after cancer treatment
Authors: Pateman Brian , Wilson Kate , McHugh Gretl , Luker Karen A. 
Published: October 2003

Background. Despite nearly three decades of debate and policy guidance there is evidence that, in the United Kingdom, patient hospital discharge remains problematic. District nurses, who deliver skilled home nursing care, receive referrals from hospitals for continuing nursing care needs. However, district nurses’ expectations of appropriate patient referral from hospitals are not always achieved. In an attempt to improve services after hospital discharge, government policy has emphasized partnership between care providers, highlighting the need for smooth transition between care settings.Aim. To explore hospital discharge and referral procedures for patients with cancer, with particular emphasis on referrals made by hospital nurses to district nurses.Method. In‐depth interviews were carried out with nurses actively involved in the discharge process as both referrers and recipients of referrals. Twenty nurses from a regional cancer centre and 20 district nurses from three adjacent primary care trusts were interviewed. Interviews were transcribed and analysed thematically, and themes compared between the two care settings.Conclusions. We conclude that competing sets of expectations, not only between hospital and community nursing settings, but amongst district nurses themselves, are a major factor impeding agreement on referral criteria and satisfaction with the referral process.
Seasonal body mass changes in Eurasian Golden Plovers Pluvialis apricaria staging in the Netherlands: decline in late autumn mass peak correlates with increase in raptor numbers
Authors: Piersma Theunis , Koolhaas Anita , Jukema Joop 
Published: October 2003

Eurasian Golden Plovers Pluvialis apricaria staging in the Netherlands during the non‐breeding season show strikingly constant seasonal changes in body mass with a first mass peak in late November and December and a second peak in late April and May. Despite huge sample sizes, variations in this pattern over successive years in the 1990s and among age classes were minuscule. However, in contrast to the body mass levels at other times of the year, there was a marked decline in the winter peak mass of Golden Plovers from the 1970s/early 1980s to 1989–2000. The decrease, by an average of 29 g, was about half the extra mass previously stored in autumn. This additional mass is known to consist of fat and may be interpreted as an energy store − insurance − for sudden cold spells when a negative energy balance forces the birds to move south and stay in front of the frostline. As the rate of the mass increase in September–October showed no change from the 1980s to the 1990s, changes in food availability are unlikely to explain the long‐term mass decline. Also, there were no differences in two factors known to influence energy expenditure and feeding rate, air temperature and rainfall. The one striking environmental change relevant to plovers was the steep increase in the occurrence of raptors in the northern Netherlands in the 1980s, notably Peregrine Falcons Falco peregrinus and Goshawks Accipter gentilis. We argue that the halving of the winter mass peak over a decade is consistent with the hypothesis that under increased risk of predation, birds lower their body mass in order to reduce individual vulnerability, a reduction that may be traded off against an increased risk of starvation.
Interspecific and intraspecific differences in two Liriomyza leafminer species in California
Authors: Reitz Stuart R. , Trumble John T. 
Published: October 2003

AbstractIn recent years, the pest status of Liriomyza trifolii (Burgess) and L. huidobrensis (Blanchard) (Diptera: Agromyzidae) has changed in California, as well as other areas of the world. In California, L. huidobrensis has become the predominant Liriomyza species in valleys along the central coast, while L. trifolii remains the predominant species in southern California. To investigate possible reasons for this change in status, differences in host plant use and reproductive success of intraspecific populations were examined for Liriomyza trifolii and L. huidobrensis from both central and southern California. The southern L. trifolii fed, oviposited and reproduced successfully on all five hosts tested, but the central population fed significantly less on all hosts and was restricted to reproducing on pepper only. With the exception of pepper, southern L. trifolii had significantly greater larval survival on all hosts than central L. trifolii. In contrast, the central L. huidobrensis population had greater reproductive success than the southern population of that species on all hosts plants tested. However, pepper was not a suitable host for either L. huidobrensis population. Both species showed positive assortative mating, with homotypic mating occurring more frequently than heterotypic mating; however, the difference between L. trifolii populations was much more pronounced than between L. huidobrensis populations. These data indicate that central and southern California populations of each species are distinct biotypes. Furthermore when coupled with previous genetic data, our results suggest the possible existence of cryptic species within L. trifolii.