Showing papers in "European Journal of Clinical Pharmacology in 1997"
TL;DR: The pharmacokinetics of orally and intravenously administered valsartan were determined in two studies and it was found that absorption appeared to follow two first-order processes.
Abstract: Objective: The pharmacokinetics of orally and intravenously administered valsartan were determined in two studies. In a first pilot study, three i.v. doses of valsartan were given in an ascending manner (5, 10 and 20 mg) to evaluate tolerability and basic pharmacokinetics of the i.v. formulation. In a second study, the absolute bioavailability of 80 mg valsartan from a capsule and a buffered solution was compared with a 20 mg i.v. dose. Methods: The concentrations of valsartan in plasma and urine were measured using HPLC. The disposition of valsartan after an i.v. dose was characterized by biphasic decay kinetics, with a distribution phase (half-life 1.0 h), followed by a longer elimination phase (half-life 9.5 h). The volume of distribution at steady state was 16.9 l, and the total body clearance 2.2 l · h−1. 29% of the i.v. dose was recovered unchanged in the urine. Results: Plasma levels peaked 2 h after oral administration of the 80 mg capsule. Thereafter, plasma levels declined biexponentially with a terminal t1/2 of 7.0 h. Cmax was reached 1 h after administration of the solution, and t1/2 was 7.5 h. On average 7.3% (capsule) and 12.6% (solution) of the dose was excreted in the urine as the unchanged drug. The fraction of dose absorbed and systemically available after oral administration was 0.23 for the capsule and 0.39 for the solution, based on AUC. Absorption appeared to follow two first-order processes. The first phase was rapid, with a half-life of 0.5 h and 0.9 h for solution and capsule, respectively. The slower absorption phase was characterized by a half-life of 6.5 h for the solution and 3.5 h for the capsule. Most of the drug was absorbed during the period 0.4 h to 3 h post-dosing, and 90% of the fraction absorbed from the capsule was absorbed within 5 h.
195 citations
TL;DR: The results of this survey demonstrate some of the advantages and disadvantages of transnational, multilingual studies of this type, but indicate that there is scope for the further development of such techniques and their use on a wider basis in the EU and elsewhere.
Abstract: Objectives: This survey was conducted to assess the attitudes of medical practitioners in the European Union regarding their national spontaneous reporting scheme, to identify reasons for under-reporting and to determine what steps might be effective in increasing reporting rates. National spontaneous reporting schemes rely on health care professionals reporting individual cases of suspected ADRs to a central or regional agency. National schemes, however, vary considerably and reporting rates and patterns differ between member states. Accumulating evidence suggests that doctors' attitudes to national ADR reporting schemes are significant determinants of reporting rates. Methods: A self-administered questionnaire and letter of invitation was sent to a random sample of approximately 1% of medical practitioners in each of nine EU member states (Denmark, France, Ireland, Italy, the Netherlands, Portugal, Spain, Sweden and the UK). One month later, a reminder letter and a second copy of the questionnaire was sent to the non-responders (except Denmark and Italy). Results: Response rates, and the percentage of responders who stated that they had reported previously an ADR, varied substantially between countries. Issues that appeared to discourage reporting included lack of availability of report forms; the address or telephone number of the reporting agency; lack of information on how to report; and not having enough time to report. Issues which did not apparently discourage reporting included concern about patient confidentiality; fear of legal liability or appearing foolish; reluctance to admit that harm had been caused to a patient; and ambition to collect and publish a personal series of cases. Conclusions: The results of this survey demonstrate some of the advantages and disadvantages of transnational, multilingual studies of this type, but indicate that there is scope for the further development of such techniques and their use on a wider basis in the EU and elsewhere.
193 citations
TL;DR: Evaluated estimators of PP in the general population based on data from a prescription database showed that an estimator based on the number of simultaneously used drugs (calculated from the date of purchase and theNumber of DDD) was robust towards changes in DDD and may also be a useful estimator.
Abstract: Objective: Concurrent use of multiple drugs (polypharmacy, PP) may cause health risks such as adverse drug reactions, medication errors and poor compliance. The objective of this study, based on data from a prescription database, was to evaluate estimators of PP in the general population. Methods: Data were retrieved from Odense Pharmacoepidemiological Database (OPED) and consisted of all prescriptions in 1994 from a 10% random sample of drug users (n=26977) in the county of Funen, Denmark. For each prescription, the period of consumption was calculated by setting the duration of treatment to equal the amount of drug purchased, as measured in defined daily doses (DDD), thereby assuming a daily intake of one DDD. PP was defined as overlapping periods of consumption for different drugs. A Venn diagram was used to illustrate and compare this estimator of PP with two other indicators of multiple-drug use: the number of drugs purchased in 3 months and the mean number of drugs used in 1 year. A receiver operating curve (ROC) was used to evaluate the possibility of predicting episodes of PP from the number of drugs purchased in 3 months. Results: The proposed estimator of PP was robust towards changes in DDD. On an average day in 1994, the prevalence of PP was 9.9% and the standard deviation (SD) between days was 0.3%. Two to four drugs (minor PP) were used by 8.7% of the population (SD, 0.2%) and five or more drugs (major PP) by 1.2% (SD, 0.1%). The number of individuals displaying PP for the first time in 1994 stabilised after approximately 6 months, resulting in an incidence of major PP of 0.2% and of minor PP of 1.2% per month. For individuals exposed to PP, the median number of days of exposure was 61 and 10.5% were exposed for more than 350 days of the year. Purchase of five or more drugs in the first 3 months of 1994 predicted episodes of major PP in the same year with a positive predictive value of 80%. Conclusion: Epidemiological measures of multiple drug use can be estimated from data in a prescription database. From a conceptual point of view, an estimator based on the number of simultaneously used drugs (calculated from the date of purchase and the number of DDD) is preferable, but the number of drugs purchased in a 3-month period may also be a useful estimator.
171 citations
TL;DR: In vivo results confirm that tramadol O-demethylation is carried out to a large extent by the polymorphic CYP2D6.
Abstract: Objective: This study was designed to investigate whether the in vivo metabolism of tramadol was influenced by CYP2D6 polymorphism.
Methods: The extent of tramadol O- and N-demethylation was calculated by determining the amounts of tramadol and O- and N-desmethyltramadol in 24 h urine after ingestion of a test dose of tramadol. The O- and N-demethylation rates were calculated by dividing the 24-h urinary excretion amount of tramadol by that of O-and N-desmethyltramadol. Volunteers were phenotyped for CYP2D6 polymorphism using sparteine as an in vivo probe.
Results and conclusion: High correlation was found between tramadol-O-demethylation and sparteine oxidation in 71 extensive metabolizers of sparteine (r
s= 0.544). The mean metabolic ratio of tramadol O-demethylation was significantly higher in poor metabolizers of sparteine than in extensive metabolizers (4.4 vs 0.8). These in vivo results confirm that tramadol O-demethylation is carried out to a large extent by the polymorphic CYP2D6.
153 citations
TL;DR: In this article, the effect of grapefruit juice on the metabolism of felodipine following intravenous and oral administration was examined, and the main effect was mediated by inhibition of gut wall metabolism.
Abstract: Objective: To examine the effect of grapefruit juice on the metabolism of felodipine following intravenous and oral administration. Methods: The study had a randomised, four-way, crossover design in 12 healthy males. Single doses of felodipine were given as an intravenous infusion for 1 h (1.5 mg) or as an oral extended release (ER) tablet (10 mg). Grapefruit juice (150 ml) or water was ingested 15 min prior to drug intake. Results: Intake of grapefruit juice did not significantly alter the intravenous pharmacokinetics of felodipine compared to control treatment, whereas after oral drug administration it did lead to an increase in the mean AUC and Cmax by 72% and 173%, respectively, and the mean absolute bioavailability was increased by 112%. The fraction of the oral felodipine dose reaching the portal system was increased from 45% to 80% when intake of drug was preceded by grapefruit juice ingestion. The pharmacokinetics of the primary metabolite, dehydrofelodipine, was affected by the intake of juice, resulting in a 46% increase in Cmax. Juice intake immediately before oral felodipine resulted in more pronounced haemodynamic effects of the drug as measured by diastolic blood pressure and heart rate. However, the haemodynamic effects of the intravenous administration were not altered by juice intake. Vascular-related adverse events were reported more frequently when oral drug administration was preceded by juice intake compared with control treatment. Taking grapefruit juice immediately prior to intravenous felodipine administration did not cause any alteration in the adverse event pattern. Conclusion: The main acute effect of the grapefruit juice on the plasma concentrations of felodipine is mediated by inhibition of gut wall metabolism.
150 citations
TL;DR: The absorption of itraconazole can be enhanced by Coca-Cola, as shown in the results of a two-way crossover design study.
Abstract: Objective: To evaluate the effectiveness of Coca-Cola in enhancing the absorption of itraconazole. Methods: Eight healthy volunteers were randomized to receive two treatment sequences in a two-way crossover design with a 1-week wash-out period separating each study treatment. Treatment I, the control, consisted of 100 mg itraconazole with 325 ml water. Treatment II was identical to treatment I, except that itraconazole was administered with 325 ml of Coca-Cola (pH 2.5). Results: Serum itraconazole concentrations, after administration with Coca-Cola (treatment II), were higher than after administration with water (treatment I). The mean AUC was 1.12 vs 2.02 μg · h · ml−1, the mean Cmax was 0.14 vs 0.31 μg · ml −1and the mean tmax was 2.56 vs 3.38 h in treatments I and II, respectively. Conclusion: The absorption of itraconazole can be enhanced by Coca-Cola.
104 citations
TL;DR: The transfer of lamotrigine taking place during pregnancy and lactation should not be neglected, but in this case the child should be thoroughly observed for potential adverse effects.
Abstract: Objective: To investigate the transfer of lamotrigine in pregnancy and during lactation from a mother on lamotrigine treatment to her child.
104 citations
TL;DR: Findings indicate that the dextromethorphan metabolic ratio has a great impact on steady-state plasma levels of DMI in depressed patients and may identify subjects at risk for severe concentration-dependent adverse effects.
Abstract: The clinical relevance of the CYP2D6 oxidation polymorphism in the treatment of depression with desipramine (DMI) was studied prospectively in depressed outpatients. After CYP2D6 phenotype determination with dextromethorphan, 31 patients were treated with oral DMI at a dosage of 100 mg per day for 3 weeks. At the end of the 3rd week of treatment, severity of depressive symptoms was assessed by the Hamilton Depression Rating Scale and steady-state plasma concentrations of DMI and its metabolite 2-hydroxydesipramine (2-OH-DMI) were measured by high-performance liquid chromatography (HPLC). Plasma DMI levels were significantly correlated with dextromethorphan metabolic ratio. The two patients with the poor metabolizer phenotype showed the highest plasma concentrations of DMI and complained of severe adverse effects, requiring dosage reduction. No significant correlation was found between plasma levels of either DMI or DMI plus 2-OH-DMI and antidepressant effect. These findings indicate that the dextromethorphan metabolic ratio has a great impact on steady-state plasma levels of DMI in depressed patients and may identify subjects at risk for severe concentration-dependent adverse effects. On the other hand, this index of CYP2D6 activity does not seem to predict the degree of clinical amelioration.
97 citations
TL;DR: The pharmacokinetics and bioavailability of artemether and dihydroartemisinin were investigated in eight Thai males following the administration of single oral and intramuscular doses ofArtemether in a randomized two-way cross-over study.
Abstract: Objective: The pharmacokinetics and bioavailability of artemether and dihydroartemisinin were investigated in eight Thai males following the administration of single oral and intramuscular doses of artemether (300 mg) in a randomized two-way cross-over study. Results: Both oral and intramuscular artemether were well-tolerated. In most cases, artemether and dihydroartemisinin were detected in plasma after 30 min and declined to levels below the limit of detection within 18–24 h. Compared with intramuscular administration, oral administration of artemether resulted in a relatively rapid but incomplete absorption [Cmax: 474 vs 540 ng · ml−1; t
max: 2.0 vs 3.9 h; AUC: 2.17 vs 5.20 μg · h · ml−1]. Geographic means of lag-time and absorption half-life (t
1/2a) of oral vs intramuscular artemether were 0.28 and 1.1 h vs 0.30 and 2 h, respectively. t
1/2z was significantly shortened after the oral dose [2.8 vs 6.9 h]. Mean oral bioavailability relative to intramuscular administration was 43.2%. The ratio of the AUCs of artemether to dihydroartemisinin was significantly lower after the oral than after the intramuscular dose (geometric mean: 0.29 vs 0.60).
91 citations
TL;DR: Thrombocytopenia induced by non-cytotoxic drugs is characterised by a heterogeneous clinical picture and recovery is generally rapid, and although corticosteroids seem inefficient, it is still recommended that severe symptomatic cases of drug-induced thrombocytes are treated as idiopathic throm bocytopenic purpura due to the difficult initial differentiation between the two conditions.
Abstract: Objective: To analyse the clinical picture and the course of thrombocytopenia induced by non-cytotoxic drugs, and to evaluate a possible therapeutic effect of corticosteroids.
88 citations
TL;DR: Investigation of whether there might be a difference between the selective serotonin re-uptake inhibitors, (SSRIs) with regard to the incidence of withdrawal reactions, and to describe the associated symptoms found it to be higher than that for sertraline and fluoxetine.
Abstract: Objective: The present study was performed both to investigate whether there might be a difference between the selective serotonin re-uptake inhibitors, (SSRIs) with regard to the incidence of withdrawal reactions, and to describe the associated symptoms. From the WHO database, therefore, all case reports from the year of introduction for each of the SSRIs, fluoxetine, paroxetine and sertraline, were retrieved. Sales figures were obtained from Intercontinental Medical Statistics International. The reporting rates were calculated as the number of reports per million defined daily doses (DDDs) sold per year.
Results: The reporting rate of withdrawal reactions for paroxetine was found to be higher than that for sertraline and fluoxetine in each of the countries selected for detailed analyses (US, UK and Australia), as well as for all 16 countries combined. Moreover, using the WHO system of organ classification, the ratio of central nervous system to psychiatric withdrawal symptoms was 1.9 and 2.1 for paroxetine and sertraline, respectively, whereas that for fluoxetine was 0.48, indicating a possible qualitative difference between the SSRIs with respect to the nature of the withdrawal syndrome.
TL;DR: The efficacy of ibuprofen was better than that of aspirin or paracetamol and in spite of more adverse events, the comfort scores were significantly in favour of ib uprofen 6 h after the first dose of treatment.
Abstract: Objective
We compared efficacy and impact on the comfort of ibuprofen (7.5 mg/kg per dose), aspirin (10 mg/kg/dose) and paracetamol (10 mg/kg per dose) on children with fever aged 6–24 months in an open, randomised study with three parallel groups.
TL;DR: The metabolism of orally administered midazolam was more strongly inhibited by oral than by intravenous administration of fluconazole, and the pharmacokinetics and pharmacodynamics of orally ingested midrazolam were significantly higher after oral than after intravenous Administration of flu Conazole.
Abstract: Midazolam is a short-acting benzodiazepine hypnotic extensively metabolized by CYP3A4 enzyme. Orally ingested azole antimycotics, including fluconazole, interfere with the metabolism of oral midazolam during its absorption and elimination phases. We compared the effect of oral and intravenous fluconazole on the pharmacokinetics and pharmacodynamics of orally ingested midazolam. A double-dummy, randomized, cross-over study in three phases was performed in 9 healthy volunteers. The subjects were given orally fluconazole 400 mg and intravenously saline within 60 min; orally placebo and intravenously fluconazole 400 mg; and or-ally placebo and intravenously saline. An oral dose of 7.5 mg midazolam was ingested 60 min after oral intake of fluconazole/placebo, i.e. at the end of the corresponding infusion. Plasma concentrations of midazolam, α-hydroxymidazolam and fluconazole were determined and pharmacodynamic effects were measured up to 17 h. Both oral and intravenous fluconazole significantly increased the area under the midazolam plasma concentration-time curve (AUC0-3, AUC0-17) 2- to 3-fold, the elimination half-life of midazolam 2.5-fold and its peak concentration (Cmax) 2- to 2.5-fold compared with placebo. The AUC0-3 and the Cmax of midazolam were significantly higher after oral than after intravenous administration of fluconazole. Both oral and intravenous fluconazole increased the pharmacodynamic effects of midazolam but no differences were detected between the fluconazole phases. We conclude that the metabolism of orally administered midazolam was more strongly inhibited by oral than by intravenous administration of fluconazole.
TL;DR: The reduction in quinine clearance in acute malaria results predominantly from a disease-induced dysfunction in hepatic mixed-function oxidase activity (principally CYP 3A) which impairs the conversion of qu inine to its major metabolite, 3-hydroxyquinine.
Abstract: Objective: To assess the factors that contribute to impaired quinine clearance in acute falciparum malaria.
TL;DR: It is concluded that many depressed patients are still not receiving antidepressant treatment and that the claimed better adverse effect profile of the newer antidepressants was not clearly reflected in their use.
Abstract: Objective: To study whether the newer antidepressants have changed the patterns of antidepressant use, and whether the claimed better adverse effect profile of the newer antidepressants is reflected in their use as monitored by a prescription database.
TL;DR: Valsartan is well tolerated and is devoid of effects on water, electrolyte and uric acid excretion at 200 mg per day in healthy normotensive volunteers, and indirect evidence of AT1 blockade by valsartans is demonstrated.
Abstract: Objective: Pharmacokinetics, pharmacodynamic effects and tolerability of 200 mg valsartan, once-daily for 8 days, were investigated in 16 healthy, normotensive volunteers on a normal sodium diet.
TL;DR: The hydroxylation of lansoprazole to 5-hydroxylansopazole was apparently impaired in the subjects with the genetic defects of CYP2C19 (m1/m1 or m1/ m2).
Abstract: Objective: We investigated whether interindividual differences in the pharmacokinetic disposition of lansoprazole are attributed to the genetic polymorphism of CYP2C19 which occurred by two mutations, CYP2C19m1 and CYP2C19m2, in 20 Japanese subjects.
TL;DR: The results are consistent with a possible minor to moderate role of CYP2D6, but not CYP1C19, in fluvoxamine metabolism.
Abstract: Objective: The purpose of this study was to investigate whether the disposition of fluvoxamine is associated with the CYP2D6 and CYP2C19 phenotype polymorphisms. Methods: The serum concentration of fluvoxamine was followed for 48 h after oral administration of a single dose of 50 mg fluvoxamine to five poor metabolizers of the CYP2D6 test drug dextromethorphan, five poor metabolizers of the CYP2C19 test drug mephenytoin, and five extensive metabolizers of both test drugs. Results: Poor metabolizers of dextromethorphan had significantly higher areas under the serum concentration-time curve than extensive metabolizers of dextromethorphan (mean 1.31 vs 1.00 μmol · h · l−1). There were no differences between poor and extensive metabolizers of mephenytoin (mean, 1.00 vs 1.15 μmol · h · l−1). Conclusion: The results are consistent with a possible minor to moderate role of CYP2D6, but not CYP2C19, in fluvoxamine metabolism.
TL;DR: The results of the present study show that FP-DH suppresses plasma cortisol more than BUD-TBH on a equivalent basis with regard to both magnitude and duration.
Abstract: Objective: To compare the systemic potency of inhaled fluticasone propionate delivered via Diskhaler® (FP-DH), and inhaled budesonide delivered via Turbuhaler® (BUD-TBH) over the clinically recommended dose range using plasma cortisol suppression as a marker for systemic activity. Methods: The systemic potency was examined in a dose-response study in 81 healthy male volunteers. The study was of an open, randomized, parallel-group (four groups) design, where two treatments were given in crossover fashion within each group. FP-DH and BUD-TBH were given b.i.d. for 7 days (14 doses): 100 and 100 μg (group 1); 200 and 200 μg (group 2); 500 and 400 μg (group 3); 1000 and 800 μg (group 4). There was a washout period of 7 days within each treatment group. All doses were administered at 08:00 and 20:00 hours. Multiple plasma cortisol samples were taken every 2 h over 24-h periods prior to randomization (baseline) and during steady state (i.e., the last two dosing intervals). Cortisol suppression was determined by comparing average plasma concentrations of cortisol before and during treatment. Dose-response curves for cortisol suppression were analyzed using multivariate non-linear regression (Hill modeling). Results: Multiple dosing for 7 days with FP-DH and BUD-TBH resulted in dose-dependent cortisol suppression by both drugs, most pronounced at the two highest dose levels. FP-DH-induced suppression was 41% at 500 μg and 86% at 1000 μg b.i.d., while that induced by BUD-TBH was 19% at 400 μg and 47% at 800 μg b.i.d. Statistically significant differences were found when comparing the two steroids at these two dose levels. Doses producing 50% of maximum suppression (ED50) were estimated at 833 μg b.i.d. for BUD-TBH and 479 μg b.i.d. for FP-DH. This gave an estimated relative cortisol suppression over the dose range of 1.74:1 (FP-DH:BUD-TBH). ED50 values, estimated from cortisol concentrations at 08:00 hours (12 h after the last dose), were 1212 μg b.i.d. for BUD-TBH and 527 μg b.i.d. for FP-DH giving a relative cortisol suppression of 2.30:1 (FP-DH:BUD-TBH). Fourteen subjects on the highest FP-DH dose and 3 at the next highest dose had morning plasma cortisol levels below the lower reference limit. No subject taking budesonide, however, had morning plasma cortisol levels below the reference limit. Analysis of the time for return to pretreatment baseline levels showed that cortisol suppression, 12–24 h after the last dose, was statistically significant compared with the baseline for the highest dose of FP-DH but not for any of the BUD-TBH doses. Conclusions: The results of the present study show that FP-DH suppresses plasma cortisol more than BUD-TBH on a equivalent basis with regard to both magnitude and duration.
TL;DR: It is reasonable to recommend that mefloquine be administered with food in travellers receiving chemoprophylaxis and in patients on recovery receiving curative treatment, and in acutely ill patients, me floquine should be taken as soon as possible and administration with or shortly after meals should be attempted.
Abstract: Objectives: To assess the effect of food on the pharmacokinetics of the antimalarial mefloquine and its major plasma metabolite in healthy volunteers.
TL;DR: Administration of grapefruit juice concomitant with terfenadine may lead to an increase in terfenADine bioavailability, but the increase observed in this study did not lead to significant cardiotoxicity in normal subjects, however, this does not exclude the risk of cardiot toxicity in high-risk subjects given greater doses of grape fruit juice over longer periods of time.
Abstract: Objective: To determine whether the pharmacokinetics and electrocardiographic pharmacodynamics of terfenadine are affected by the concomitant administration of grapefruit juice.
TL;DR: Although it is accepted that self-reporting of poor compliance is generally lower than actual poor compliance, the present risk model provides further insight into the drug-taking habits of elderly patients.
Abstract: Objective: To assess self-reported compliance with prescribed medications in a population of elderly patients prior to their hospital admission in an attempt to understand further the factors which influence drug-taking patterns.
Methods: Information which, based on personal clinical experience and published research, may impact on compliance was collected for patients by way of a chart review within 3 days of hospital admission, a search of patient computerised hospital records and an interview. All crude data were coded and entered into a computerised relational database. Each patient's data were assessed using the Naranjo algorithm and the score was recorded. Chi-square analysis highlighted those factors which significantly influenced compliance, sub-divided into under-compliance (taking less medicine than prescribed) and over-compliance (taking more medicine than prescribed). Inter-relationships between variables were investigated using multiple-regression analysis.
Results: Overall, 13.7% of the population (n=512) reported non-compliance, with 10.7% reporting under-compliance and 4.3% reporting over-compliance. A number of patients reported both under- and over-compliance. Being prescribed bronchodilators, for example, was found to be associated with under-compliance, while being prescribed analgesics (excluding non-steroidal anti-inflammatories) was associated with over-compliance using Chi-square analysis. A five-variable non-compliance risk model was obtained from logistic regression analysis. This model had a specificity of 88.9% and a sensitivity of 33.3%. The factors shown to influence compliance were the type of drug being taken (diuretics, bronchodilators and benzodiazepines), independence when taking medicines and the number of non-prescription drugs being taken. All other laboratory/test data, diseases/diagnoses, reasons for hospital admission and socio-demographic factors were not significant risk factors for self-reported non-compliance in the present model.
Conclusions: Although it is accepted that self-reporting of poor compliance is generally lower than actual poor compliance, the present risk model provides further insight into the drug-taking habits of elderly patients.
TL;DR: Fluvastatin therapy had lipid-lowering and antioxidative effects and the change of the lagtime did not reach significance; however, it was positively correlated with the change in LDL α-tocopherol.
Abstract: Objective: Oxidation of low density lipoproteins (LDL) is thought to be an important step in the development of atherosclerosis. Trace metals are involved in oxidative processes. It was of interest to determine whether lipid-lowering therapy with fluvastatin, a potent HMGCoA reductase inhibitor, affected LDL oxidation and trace metal levels.
TL;DR: Treatment with phenylephrine increased expected haemodynamic parameters in a linear fashion; however, clinical changes in VO2I occurred at variable doses, and dose-response trials are needed to determine the optimal dose.
Abstract: Objective: To determine the response of haemodynamic and oxygen-transport parameters to phenylephrine in a dose-response fashion in septic non-hypotensive, vasodilated surgical intensive care unit (ICU) patients. Design: Prospective study. Setting: Surgical ICU of a tertiary care, university medical centre. Patients: Ten septic non-hypotensive, vasodilated surgical ICU patients. Interventions: Routine ICU monitoring, including pulmonary and radial artery catheters. Measurements: Haemodynamic and oxygen-transport measurements were taken at baseline and during therapy. Phenylephrine was infused intravenously for 3 h at progressively increasing doses of 0.5, 1.0, 2.0, 3.0, 4.0, and 8.0 μg · kg−1 · min−1 at 30-min intervals. Measurements were taken after each dose. Results: Mean arterial pressure (MAP) and systemic vascular resistance (SVRI) increased linearly with phenylephrine dose. Cardiac index and pulmonary artery occlusion pressures did not change. Statistically significant changes were observed in heart rate, MAP, stroke index, and systemic and pulmonary vascular resistance. Eight patients had a clinically significant increase (>15%) in oxygen consumption (VO2I). Oxygen delivery (D2OI) increased in only three patients. Serum lactate concentrations were unchanged or lower at the end of the study in all eight pateints, who displayed a 15% increase in VO2I. Conclusions: Treatment with phenylephrine increased expected haemodynamic parameters in a linear fashion; however, clinical changes in VO2I occurred at variable doses. Dose-response trials are needed to determine the optimal dose of phenylephrine. Further study is needed to evaluate the clinical effects of phenylephrine in septic patients.
TL;DR: Multiple cytochrome P450 isoforms (P450 1A2, 2C8 and 2C9) appear to be involved in naproxen demethylation, although 2C 9 appears to be the predominant form.
Abstract: Objective: A series of studies was undertaken to determine the cytochrome P450 isoform(s) involved in naproxen demethylation and whether this included the same isoforms reported to be involved in the metabolism of other NSAIDs. Methods: (S)-Naproxen was incubated with human liver microsomes in the presence of a NADPH-generating system and the formation of desmethylnaproxen was measured by high-performance liquid chromatography (HPLC). To further clarify the specific isoforms involved, experiments were conducted with preparations expressing only a single P450 isoform (vaccinia virus-expressed cells and microsomes derived from a lymphoblastoid cell line, each transfected with specific P450 cDNAs) as well as inhibition studies using human liver microsomes and putative specific P450 inhibitors. Results: In human liver microsomes (n=7), desmethylnaproxen formation was observed with a mean kM of 92 (21) μmol · l−1, Vmax of 538 pmol · min−1 · mg−1 protein and Cint2 (reflective of a second binding site) of 0.36 μl · min−1 · mg−1 protein. This Cint2 term was added since Eadie-Scatchard analysis suggested the involvement of more than one enzyme. Studies using putative specific P450 inhibitors demonstrated inhibition of this␣reaction by sulfaphenazole, (apparent Ki= 1.6 μmol · l−1), warfarin (apparent Ki=27 μmol · l−1), piroxicam (apparent Ki=23 μmol · l−1) and tolbutamide (apparent Ki=128 μmol · l−1). No effect was observed when α-naphthoflavone and troleandomycin were employed as inhibitors, but reaction with furafylline produced, on average, a maximum inhibition of 23%. At a naproxen concentration of 150 μmol · l−1, formation of desmethylnaproxen was observed in cells expressing P450 1A2, 2C8, 2C9 and its allelic variant 2C9R144C. To further characterize these reactions, saturation kinetics experiments were conducted for the P450s 1A2, 2C8 and 2C9. The kM and Vmax for P450 1A2 were 189.5 μmol · l−1 and 7.3 pmol · min−1 · pmol−1 P450, respectively. Likewise, estimates of kM and Vmax for P450 2C9 were 340.5 μmol · l−1 and 41.4 pmol · min−1 · pmol−1 P450, respectively. Reliable estimates of kM and Vmax could not be made for P450 2C8 due to the nonsaturable nature of the process over the concentration range studied. Conclusion: Multiple cytochrome P450 isoforms (P450 1A2, 2C8 and 2C9) appear to be involved in naproxen demethylation, although 2C9 appears to be the predominant form.
TL;DR: The distribution of nebivolol in the adipose tissue in obese subjects is limited, despite its high lipophilicity, and the pharmacokinetic parameters of the separate unchanged enantiomers were similar to those of the racemate in both groups.
Abstract: Objective: The pharmacokinetics of a single i.v. dose of the new racemic β-adrenoceptor-blocker nebivolol [0.073 mg base · kg–1 ideal body weight (IBW)] was studied in 9 obese (157% IBW) and 9 non-obese healthy volunteers (98% IBW). Each group contained 4 men and 5 women, aged 32 years, including one poor hydroxylator (dextrometorphan test).
TL;DR: The results of the survey showed that German hospital drug committees vary considerably with regard to their function and control mechanisms of drug use.
Abstract: Objectives: Hospital drug committees have been established to ensure rational drug use. However, with regard to their structure and duties remarkable differences between European countries may exist, reflecting the differences in drug legislation and market. Our aim was to obtain information about the structure, present activities and decision-making processes of hospital drug committees in Germany and especially the role of clinical pharmacologists in these committees.
TL;DR: Computerised on-line monitoring and automatic alarming of potentially hazardous drug combinations might help clinicians to prescribe more safely, but further development of the system is needed to avoid unnecessary alarms.
Abstract: Objective: Drug interactions may lead to life-threatening injuries. More often, however, they lead to slow recovery, induce slight symptoms or result only in potential injury. Therefore, clinicians are not always aware of using potentially interacting drug combinations. An on-line alarming system of potential drug interactions was developed in Turku University Central Hospital. In the present study, we utilised the system to find out the incidence and nature of potential drug interactions occurring in a representative hospital patient population. Methods: Computerised anatomical therapeutic chemical (ATC)-coded patient medication data of 2547 patients, treated in two internal medicine wards, were combined with an ATC-coded rule base of drug interactions. All potential drug interactions in the study population were searched for. Results: A total of 326 potentially serious drug interactions were detected in the study population. The number of patients in this group was 173, i.e. 6.8% of all patients had one or several drug combinations which might have led to serious clinical consequences. Concomitant use of calcium and fluoroquinolones (decreased absorption) was the most common mistake (66 prescriptions). Conclusions: Potentially inappropriate drug combinations seem to occur frequently. Structured and coded medication data can be utilised efficiently to detect potential drug interactions in hospital. Computerised on-line monitoring and automatic alarming of potentially hazardous drug combinations might help clinicians to prescribe more safely, but further development of the system is needed to avoid unnecessary alarms.
TL;DR: The data show valsartan 80 mg to be as effective as HCTZ in the treatment of mild-to-moderate essential hypertension and to be well tolerated when taken alone or in combination with atenolol.
Abstract: Objective: To compare the antihypertensive efficacy of a new angiotensin II antagonist, valsartan, with a reference therapy, hydrochlorothiazide (HCTZ).
TL;DR: Nebivolol has no additional α1-blocking property, which may at least in part explain its vasodilating effect, and β1-Blockade of nebivoll 5 mg is larger after repeated dosing than after a single oral intake.
Abstract: The aims of the present study were to determine (1) the β1-blocking potency and (2) the β1 adrenoceptor selectivity of nebivolol in man after repeated dosing (7 days) compared with that after a single oral intake and with that after atenolol for 7 days. In addition, it was investigated whether (3) nebivolol has α1-blocking properties which might at least in part explain the vasodilating property of the compound. Twelve healthy subjects were randomized in an open, two-way cross-over study. β1-Blocking potency and β1-adrenoceptor selectivity of nebivolol 5 mg once daily (o.d.) were compared with those of atenolol at three doses (25, 50 and 100 mg) o.d. Measurements were performed after 1 and 7 days of drug intake. β1Adrenoceptor potency was assessed by the percentage decrease in exercise-induced tachycardia (AEIT) during β-blockade. β1-Selectivity of nebivolol and atenolol were investigated using the heart rate response to isoprenaline at equipotent β1blocking dosages of both drugs. α1-Blockade of nebivolol was measured using the phenylephrine dose-response test. ΔEIT after a single oral dose of nebivolol 5 mg (10%) was significantly smaller than after nebivolol 5 mg o.d. for 7 days (15%). After 1 week of treatment no difference was seen in ΔEIT between nebivolol 5 mg o.d. and atenolol 25 mg o.d. (16%). At these dosages the suppression in isoprenaline-induced tachycardia by both drugs did not differ (CD20 ratio 1.7). In contrast to atenolol 25 mg, after 1 week of nebivolol 5 mg o.d., blood pressure decreased. This decrease averaged 10% and — like in a study with hypertensive patients — was similar with that after atenolol 100 mg o.d. None of the phenylephrine test parameters changed from pre-study values after nebivolol. β1-Blockade of nebivolol 5 mg is larger after repeated dosing than after a single oral intake. After once daily repeated dosing nebivolol 5 mg and atenolol 25 mg are equipotent in β1-antagonism. No difference in β1-selectivity is observed between the two drugs. Nebivolol has no additional α1-blocking property, which may at least in part explain its vasodilating effect.