bluuebunny/crossref_metadata_2025_split huggingface dataset:
Increase in force of contraction by activation of the Na+‘ox/Ca2+‘ox‐exchangerin human myocardium
Authors: Müller‐Ehmsen Jochen , Frank Konrad , Brixius Klara , Schwinger Robert H. G. 
Published: October 2003

Aims The aim of the present study was to investigate whether agents which enhance force of contraction via increasing intracellular Na+, i.e. cAMP‐independently, remain effective in failing human myocardium.
Methods Cumulative concentration‐response curves with (±)BDF 9148 (0.01–10 μmol l−1 ), a Na+‐channel activator, and ouabain (0.01–0.1 μmol l−1 ), a Na+/K+‐ATPase inhibitor, were performed on electrically driven left ventricular human papillary muscle strips (1 Hz, 37° C; dilative cardiomyopathy, NYHA IV, heart transplantation, n=16; nonfailing, donor hearts, n=5). The β‐adrenoceptor agonist isoprenaline (0.001–1 μmol l−1 ) and Ca2+ (1.8–15 mmol l−1 ) were studied for control. In addition, Ca2+ response curves were obtained on skinned fibre preparations from left ventricular myocardium (NYHA IV, n=7) in the presence of BDF 9148 (1 μmol l−1 ) or a high Na+ concentration (50 mmol l−1 ) to investigate a possible direct or indirect interaction of (±)BDF 9148 with the myofilaments.
Results While isoprenaline was significantly less effective in increasing force of contraction in failing human myocardium than in nonfailing myocardium (P<0.01), in NYHA IV, (±)BDF 9148 and ouabain were as effective as in nonfailing human tissue. In failing and nonfailing myocardium, (±)BDF 9148 and ouabain exerted positive inotropic effects similar to those of Ca2+. However, the potency for (±)BDF 9148 to increase force of contraction was higher in NYHA IV than in nonfailing human myocardium (P<0.05). Neither (±)BDF 9148 (1 μmol l−1 ) nor an increased concentration of Na+ (50 mmol l−1 ) altered the Ca2+ sensitivity or maximal developed tension of the contractile apparatus in experiments on chemically skinned left ventricular fibres.
Conclusions The enhanced sensitivity of the failing human myocardium towards Na+‐channel modulation is not due to a direct or indirect interaction of (±)BDF 9148 with cardiac myofilaments but may be due to an altered Na+‐homeostasis in human heart failure.
Lack of inhibitory effect of cimetidine on caffeine metabolism in children using the caffeine breath test
Authors: Parker A.C. , Pritchard P. , Preston T. , Dalzell A.M. , Choonara I. 
Published: October 2003

Aims To study the potential drug interaction between cimetidine and caffeine in a group of children who received cimetidine for gastritis. Methods The caffeine breath test was carried out prior to the administration of cimetidine and after 2–3 weeks therapy. The children (n=1) received 300–800 mg cimetidine daily (11–36 mg kg−1 day−1 ). Results There was no significant change in the 2 h cumulative labelled CO2 following the administration of cimetidine (mean values 5.61% before and 4.87% during cimetidine; Student’s t‐test P >0.2). Conclusions Cimetidine did not have an inhibitory effect on the metabolism of caffeine in this group of children studied.
Venlafaxine: in vitro inhibition of CYP2D6 dependent imipramine and desipramine metabolism; comparative studies with selected SSRIs, and effects on human hepatic CYP3A4, CYP2C9 and CYP1A2
Authors: Ball Simon E. , Ahern Dennis , Scatina Joann , Kao John 
Published: October 2003

Aims In order to anticipate drug‐interactions of potential clinical significance the ability of the novel antidepressant, venlafaxine, to inhibit CYP2D6 dependent imipramine and desipramine 2‐hydroxylation was investigated in human liver microsomes. The data obtained were compared with the selective serotonin re‐uptake inhibitors, fluoxetine, sertraline, fluvoxamine and paroxetine. Venlafaxine’s potential to inhibit several other major P450s was also studied (CYP3A4, CYP2D6, CYP1A2).Methods Ki values for venlafaxine, paroxetine, fluoxetine, fluvoxamine and sertraline as inhibitors of imipramine and desipramine 2‐hydroxylation were determined from Dixon plots of control and inhibited rate data in human hepatic microsomal incubations. The inhibitory effect of imipramine and desipramine on liver microsomal CYP2D6 dependent venlafaxine O‐demethylation was determined similarly. Venlafaxine’s IC50 values for CYP3A4, CYP1A2 CYP2C9 were determined based on inhibition of probe substrate activities (testosterone 6β‐hydroxylation, ethoxyresorufin O‐dealkylase and tolbutamide 4‐hydroxylation, respectively).Results Fluoxetine, paroxetine, and fluvoxamine were potent inhibitors of imipramine 2‐hydroxylase activity (Ki values of 1.6±0.8, 3.2±0.8 and 8.0±4.3 μm, respectively; mean±s.d., n=3), while sertraline was less inhibitory (Ki of 24.7±8.9 μm ). Fluoxetine also markedly inhibited desipramine 2‐hydroxylation with a Ki of 1.3±0.5 μm. Venlafaxine was less potent an inhibitor of imipramine 2‐hydroxylation (Ki of 41.0±9.5 μm ) than the SSRIs that were studied. Imipramine and desipramine gave marked inhibition of CYP2D6 dependent venlafaxine O‐demethylase activity (Ki values of 3.9±1.7 and 1.7±0.9 μm, respectively). Venlafaxine did not inhibit ethoxyresorufin O‐dealkylase (CYP1A2), tolbutamide 4‐hydroxylase (CYP2C9) or testosterone 6β‐hydroxylase (CYP3A4) activities at concentrations of up to 1 mm.Conclusions It is concluded that venlafaxine has a low potential to inhibit the metabolism of substrates for CYP2D6 such as imipramine and desipramine compared with several of the most widely used SSRIs, as well as the metabolism of substrates for several of the other major human hepatic P450s.
Natriuretic efficiency of frusemide as a consequence of drug input rate
Authors: Wakelkamp Monique , Alván Gunnar , Paintaud Gilles 
Published: October 2003

Aims  The aim of the present study was to investigate the influence of the rate of delivery of frusemide to its site of action on the effect and efficiency of the drug. Methods  Frusemide 30 mg was administered as a bolus dose, a slow‐rate infusion and a bolus dose in combination with 2 g of probenecid in a three way cross‐over design to seven healthy volunteers. Urinary volume and contents of frusemide and sodium were measured in samples collected over 10 h. Results
Total natriuretic response was 40% higher (P<0.001) after the infusion and 20% higher (P<0.05) after the combined treatment with probenecid, as compared with the bolus dose. Total natriuretic efficiency did not differ between the infusion (0.013 mmol μg−1 ) and the combined treatment with probenecid (0.015 mmol μg−1 ), but was significantly higher as compared with the bolus dose (0.009 mmol μg−1 ). Natriuretic effect data were modeled according to the sigmoid Emax model and the frusemide excretion rate with maximum efficiency (EReffmax) was calculated from the estimated parameters. For both the frusemide infusion and the combined treatment with probenecid, the time course of delivery of frusemide into the urine consistently approached EReffmax more closely than was the case for the bolus dose. The natriuretic effect vs frusemide excretion rate curves were shifted to the right, and the estimated values of the sigmoid Emax model were higher for EC50 and lower for the slope factor after the bolus dose, which may indicate tolerance development for this treatment. Conclusions  Slowing the delivery of frusemide to the site of action increased the efficiency of the drug, leading to an increased natriuretic response.
The peptide endothelin receptor antagonist, TAK‐044, produces sustained inhibition of endothelin‐1 mediated arteriolar vasoconstriction
Authors: Ferro C. J. , Haynes W. G. , Johnston N. R. , Lomax C. C. , Newby D. E. , Webb D. J. 
Published: October 2003

Aims Endothelin‐1 (ET‐1) has been implicated in the pathophysiology of a number of cardiovascular diseases for which endothelin receptor antagonists are currently under clinical development. We have previously reported that systemic administration of the combined endothelin A/B receptor antagonist, TAK‐044, abolishes the forearm vasoconstriction caused by intrabrachial ET‐1 infusion for at least 3 h. In this study we investigated whether TAK‐044 can inhibit ET‐1 mediated forearm vasoconstriction for longer periods. Methods Eighteen subjects were recruited to a randomized, placebo‐controlled, single‐blind, three‐way, crossover study. Subjects were divided into three groups of six. Groups received 25 mg, 50 mg or 100 mg TAK‐044 on two separate occasions, 6 and 10 h before the start of a 2 h intrabrachial infusion of ET‐1 (5 pmol min−1 ). On a third occasion subjects received only placebo before intra‐arterial ET‐1 infusion. Forearm vasoconstriction to ET‐1 was measured by venous occlusion plethysmography. Results In the placebo phase, ET‐1 caused significant, slowly‐progressive local forearm vasoconstriction of ∼30% (P<0.01) in all three groups. All three doses of TAK‐044, administered at both timepoints, tended to blunt the vasoconstriction caused by ET‐1. When the responses from all three groups were combined, TAK‐044 significantly reduced ET‐1 mediated vasoconstriction compared with placebo −9% (95% CI −15 to −3; P=0.01) at 8 h and by −9% (95% CI −17 to −2; P=0.01) 12 h after dosing. Conclusions TAK‐044 attenuated, but did not abolish, local ET‐1 mediated vasoconstriction, for up to 12 h after administration. Vasoconstriction to local intra‐arterial administration of ET‐1 appears to represent a safe and reproducible pharmacodynamic index of systemic endothelin receptor antagonism in humans.
Compliance with a 2 day course of artemether‐mefloquine in an area of highly multi‐drug resistant Plasmodium falciparum malaria
Authors: Na‐Bangchang K. , Congpuong K. , Sirichaisinthop J. , Suprakorb K. , Karbwang J. 
Published: October 2003

Aims Multi‐drug resistant Plasmodium falciparum malaria is a rapidly increasing problem in the world, particularly Thailand. Practical antimalarial regimens which are highly effective against multi‐drug resistant parasites with short‐term course of administration are needed. In this study, we assessed the patient compliance of a short course regimen using artemether‐mefloquine.Methods Clinical effectiveness (efficacy, tolerability and patient compliance) of a 2‐day regimen of artemether‐mefloquine was evaluated in 126 patients with acute uncomplicated falciparum malaria who were attending the two malaria clinics in an area of highly multi‐drug resistant P. falciparum malaria (Thai‐Myanmar border). Patients were treated with a single oral dose of 300 mg artemether on the day of attendance. Two additional doses of mefloquine were given for home treatment on the following day (750 and 500 mg after breakfast and lunch, respectively).Results The combination regimen was effective, with a cure rate of 92.6%. Based upon the concentrations of whole blood mefloquine on day‐2, compliance for this 2 day regimen of artemether‐mefloquine was 98.1% (full compliance 86.8%, partial compliance 11.3%, non‐compliance 1.9%).Conclusions We conclude that the 2 day regimen of artemether‐mefloquine is, at present, a good alternative regimen for the treatment of uncomplicated multi‐drug resistant falciparum malaria.
Lack of effect of eprosartan on the single dose pharmacokinetics of orally administered digoxin in healthy male volunteers
Authors: Martin D. E. , Tompson D. , Boike S. C. , Tenero D. , Ilson B. , Citerone D. , Jorkasky D. K. 
Published: October 2003

Aims To study the effect of eprosartan, a nonbiphenyl tetrazole angiotensin II receptor antagonist, on digoxin pharmacokinetics in a randomized, open‐label, two period, period balanced crossover study in 12 healthy men.Methods Each subject received a single 0.6 mg oral dose of digoxin (Lanoxicaps® 0.2 mg/capsule, Glaxo Wellcome) alone or following 4 days of dosing with eprosartan 200 mg orally every 12 h. Each study period was separated by a 14 day washout interval. Serial blood samples were obtained for up to 96 h after each digoxin dose for determination of digoxin pharmacokinetics. The effect of eprosartan on digoxin pharmacokinetics was assessed through an equivalence‐type approach using AUC(0, t′) as the primary endpoint.Results For AUC(0, t′), the ratio of digoxin+eprosartan:digoxin alone was 0.99 with a 90% confidence interval (CI) of [
0.90, 1.09]. For Cmax, the ratio was 1.00 with a 90% CI of [0.86, 1.17]. tmax was similar for both regimens. Both regimens were safe and well tolerated.Conclusions Based on AUC and Cmax data, it can be concluded that eprosartan has no effect on the pharmacokinetics of a single oral dose of digoxin.
Haemodynamic effects of adrenomedullin in human resistance and capacitance vessels
Authors: Cockcroft John R. , Noon Joseph P. , Gardner‐Medwin Janet , Bennett Terry 
Published: October 2003

Aims The haemodynamic effects of adrenomedullin and calcitonin gene‐related peptide (CGRP) were studied in resistance and capacitance vessels of healthy volunteers. Methods Adrenomedullin and CGRP were infused into the brachial artery of eight healthy subjects on two separate occasions at doses between 0.3–30 pmol min−1. Forearm blood flow was measured using venous occlusion plethysmography. Venodilatation to adrenomedullin and CGRP was assessed in a further eight subjects by infusing the peptides at doses between 0.3–10 pmol min−1 into a dorsal hand vein preconstricted with noradrenaline. Venodilator responses were measured as percentage reduction in noradrenaline preconstriction. Results Adrenomedullin and CGRP at a dose of 30 pmol min−1, produced an increase in forearm blood flow of 288±42% and 252±30% respectively (mean±s.e. mean, P<0.001). At doses between 3 and 10 pmol min−1 adrenomedullin was significantly more potent than CGRP. The vasodilatation to both peptides was of similar duration with a biological half‐life of approximately 18 min. Adrenomedullin reversed constriction in dorsal hand veins by 84±2% (P<0.001) at a dose of 10 pmol min−1. CGRP produced a similar effect reversing constriction by 72±12% at the same dose (P<0.01). In veins, adrenomedullin was also more potent than CGRP at doses between 0.3 and 3 pmol min−1. Conclusions The lowest dose of adrenomedullin producing significant arteriolar dilatation was calculated to produce plasma levels similar to those found in heart failure. These findings suggest that in pathophysiological conditions such as heart failure circulating levels of adrenomedullin may be within a range capable of influencing vascular resistance directly.
Differential inhibition of cytochrome P450 isoforms by the protease inhibitors, ritonavir, saquinavir and indinavir
Authors: Eagling V. A. , Back D. J. , Barry M. G. 
Published: October 2003

Aims To compare the inhibitory potential of the HIV protease inhibitors saquinavir, ritonavir and indinavir against CYP1A2, CYP2C9, CYP2E1 and CYP3A4 catalysed metabolic reactions in human liver microsomes in vitro.Methods Microsomes from six human livers were utilized in this study. The probe substrates were phenacetin (CYP1A2), tolbutamide (CYP2C9), chlorzoxazone (CYP2E1) and testosterone (CYP3A4). Metabolites were analysed by high performance liquid chromatography. IC50 (concentration of inhibitor giving 50% decrease in enzyme activity) and, where appropriate, Ki values were calculated.Results Ritonavir was a very potent inhibitor of CYP3A4 mediated testosterone 6β‐hydroxylation (mean Ki=0.019±0.004 μm, mean±s.d.; n=6) and also inhibited tolbutamide hydroxylation (IC50=4.2±1.3 μm, mean±s.d.; n=6). Inhibition of phenacetin O‐deethylation and chlorzoxazone 6‐hydroxylation was negligible. Indinavir was an order‐of‐magnitude less potent in inhibiting CYP3A4 (Ki=0.17±0.01 μm ) and did not produce appreciable inhibition of the CYP1A2, CYP2C9 or CYP2E1 catalysed reactions. Saquinavir was the least potent CYP3A4 inhibitor (Ki=2.99±0.87 μm ) and produced some inhibition of CYP2C9 (approximately 50% at 50 μm ).Conclusions The HIV protease inhibitors have differential effects on CYP isozymes. There is obviouspotential for clinically significant drug interactions particularly with ritonavir. Pharmacokinetic drug interaction studies are crucial to gain an overall understanding of the beneficial and potentially harmful effects of this important group of drugs.
Effect of melatonin and metabolites on copper‐mediated oxidation of low density lipoprotein
Authors: Seeger Harald , Mueck Alfred O. , Lippert Theodor H. 
Published: October 2003

Aims A prophylactic use of melatonin as an anti‐ageing drug has recently gained public interest due to its radical scavenging property in vitro. The present study was designed to investigate a possible antiatherogenic effect of melatonin and its physiological metabolites by examining their action on the radical‐initiated formation of oxidized LDL, which is known to possess a high atherogenic potency. The metabolites investigated were the precursors serotonin and N‐acetyl‐serotonin and the main breakdown product 6‐hydroxymelatonin. Methods The effect of the test substances on the in vitro oxidation of LDL (increase in conjugated diene formation) was investigated at concentrations of 1, 5, and 10 &mu;m. Results Melatonin increased the lag time of formation of oxidized LDL only at a concentration of 10 &mu;m. In contrast, 6‐hydroxymelatonin, serotonin and N‐acetyl‐serotonin as well as vitamin E showed inhibitory effects starting at 1 &mu;m. Thus the antioxidative action of melatonin was negligible compared with the effect of its main metabolite, its precursors and of vitamin E. Conclusions The present results indicate that the pineal hormone melatonin appears to have little antiatherogenic property as regards the oxidation of LDL. Its main breakdown product 6‐hydroxymelatonin, however, inhibits LDL‐oxidation comparable to vitamin E. The precursors of melatonin, N‐acetyl‐serotonin and serotonin may also play a role in the inhibition of LDL oxidation in vivo.
Effect of troleandomycin on the pharmacokinetics of imipramine in Chinese: the role of CYP3A
Authors: Wang Jun‐Sheng , Wang Wei , Xie Hong‐Guang , Huang Song‐Lin , Zhou Hong‐Hao 
Published: October 2003

Aims In vitro data indicate that imipramine (IMI), a widely used tricyclic antidepressant drug, is N‐demethylated by several isoforms of cytochrome P450, which include CYP3A4. The aim of this study was to investigate the role of CYP3A in the in vivo N‐demethylation of IMI.Methods Healthy subjects were given troleandomycin (TAO), a selective inhibitor of CYP3A, 250 mg daily for 2 days before a single oral dose of 100 mg IMI was administered.Results Pretreatment with TAO significantly increased the AUC of IMI by 59% (1971±938 vs 3134±2000 μg l−1 h, 95% confidence interval for difference between means: 218 to 2108 μg l−1 h, P<0.05) and decreased its oral clearance by 30% (60.9±27.4 vs 42.5±22.7 l h−1, 95% confidence internal for difference between means: 7.2 to 31.7 l h−1, P<0.05).Conclusions We conclude that CYP3A may play an important role in the in vivo N‐demethylation of IMI.
The effect of age on plasma MEGX concentrations
Authors: Orlando R. , Palatini P. 
Published: October 2003

Aims The study was designed to assess the effect age on the monoethylglycinexylidide (MEGX) liver function test.Methods Plasma MEGX concentration was measured in 16 young and 17 elderly healthy volunteers 10, 15, 30, 45 and 60 min after intravenous injection of 1 mg kg−1 lignocaine.Results Lower MEGX concentrations were noted in elderly subjects. The difference between young and old individuals became increasingly significant as the sampling time was increased, mainly because of a progressive decrease in intersubject variability within each of the two study groups. Linear regression analysis consistently showed that the strength of the relationships between MEGX concentration and age increased with increased sampling time and was maximal at 60 min (r=−0.70; P<0.0001; reduction in MEGX formation (95% CI) 0.51 (0.33–0.69) ng ml−1 per year).Conclusions These data indicate that the rate of MEGX production declines significantly with age. Therefore, when the results of the MEGX test are to be compared in different study groups, subjects should be strictly matched for age.
Tamoxifen metabolic patterns within a glioma patient population treated with high‐dose tamoxifen
Authors: Ducharme Julie , Fried Karen , Shenouda George , Leyland‐Jones Brian , Wainer Irving W. 
Published: October 2003

Aims The study was designed to evaluate tamoxifen metabolic profiles in 25 patients (13 M, 12 F) suffering from recurrent high‐grade cerebral astrocytomas who were treated with high oral doses of tamoxifen (120 mg/m2 twice daily). Methods Tamoxifen was administered for at least 8 weeks; after 4 weeks blood samples were collected 7 h post dose. Tamoxifen and metabolites were analysed by h.p.l.c. Results Steady‐state plasma concentrations (mean μm±s.d.) were determined for tamoxifen (2.94±3.44), N‐desmethyltamoxifen (4.37±2.13), N‐desdimethyltamoxifen (1.49±0.54), 4‐hydroxytamoxifen (0.13±0.05) and tamoxifen primary alcohol (1.07±0.46). Male and female patients had comparable metabolic profiles, both qualitatively and quantitatively. The mean plasma tamoxifen concentrations were higher in dexamethasone‐treated patients than untreated patients: 3.94±4.35 μm (95% C.I.: 1.43–6.46) vs 1.67±0.84 μm (95% C.I.: 1.11–2.24), with vs without; while phenytoin‐treated patients had lower concentrations: 1.85±0.87 μm (95% C.I.: 1.37–2.34) vs 4.58±5.05 μm (95% C.I.: 0.97–8.19), with vs without. The differences approached but did not reach statistical significance (P=0.065 and 0.078 respectively). Conclusions There was marked interpatient variability. The observed effect of dexamethasone on tamoxifen concentrations is consistent with the involvement of CYP3A in metabolism.
The effect of omeprazole on the pharmacokinetics of metronidazole and hydroxymetronidazole in human plasma, saliva and gastric juice
Authors: Jessa M. J. , Goddard A. F. , Barrett D. A. , Shaw P. N. , Spiller R. C. 
Published: October 2003

Aims To evaluate the effect of omeprazole on the pharmacokinetics of metronidazole and hydroxymetronidazole in plasma, gastric juice and saliva following intravenous infusion or oral dosing of metronidazole. Methods Eight volunteers received single doses of metronidazole (400 mg) intravenously and orally, whilst taking placebo or omeprazole (40 mg, twice daily for 5 days) in a randomized 4‐way crossover study. Metronidazole and hydroxymetronidazole concentrations in plasma, saliva and gastric juice samples were determined by h.p.l.c. Pharmacokinetic parameters for metronidazole and hydroxymetronidazole were calculated, and the significance of the mean differences in parameters between omeprazole and placebo co‐administration was assessed using a two‐tailed, paired t‐test. Results There were no significant differences (P<0.05) in any of the plasma or saliva pharmacokinetic parameter values for metronidazole between volunteers receiving omeprazole or placebo when metronidazole was administered either as an intravenous infusion or orally. Following intravenous administration of metronidazole to the placebo group and omeprazole treated group respectively, the gastric transfer of metronidazole was significantly reduced from 15.5±10.4% to 2.6±1.0% of the dose (P=0.007; 95% CI of difference 4.8 to 21.0) with concomitant changes in the metronidazole AUC (from 77.5±18.0 &mu;mol l−1 h to 352.6±182.1 &mu;mol l−1 h; P=0.0003; 95% CI of difference 127.6 to 422.7), Cmax (from 61.4±26.5 &mu;mol l−1 to 271.8±104.3 &mu;mol l−1; P=0.0001; 95% CI of difference 118.6 to 302.1). Similarly, the gastric juice AUC of hydroxymetronidazole was significantly reduced from 3.2±1.9 &mu;mol l−1 h to 1.5±0.8 &mu;mol l−1 h of the dose (P=0.0043; 95% CI of difference 0.4 to 3.0) with a concomitant change in Cmax (from 5.0±2.5 &mu;mol l−1 to 3.0±1.2 &mu;mol l−1; P=0.0007; 95% CI of difference 0.7 to 3.4). Conclusions Omeprazole had little effect on the plasma and salivary pharmacokinetics of metronidazole (or its hydroxymetabolite) after intravenous or oral administration, but it did have a substantial effect on the pharmacokinetics of metronidazole and hydroxymetronidazole in gastric juice.