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European Journal of Clinical Pharmacology (v.58, #10)

The skin vasoconstrictor assay does not correlate significantly to airway or systemic responsiveness to inhaled budesonide in asthmatic patients by Andrew M. Wilson; Wendy J. R. Coutie; Erika J. Sims; Brian J. Lipworth (pp. 643-647).
Objective. The responsiveness to inhaled corticosteroid varies among individual asthmatic patients. It is not known, however, whether the effects of corticosteroids on one bodily tissue reflect the response in another in a given individual. The aim was to a assess whether skin vasoconstrictor assay might predict airway and systemic tissue responsiveness to inhaled budesonide in patients with asthma. Methods. Twenty-two patients with mild to moderate persistent asthma previously enrolled in a dose–response study assessing the effects of inhaled budesonide on airway bronchial challenge testing, exhaled nitric oxide and blood cortisol and eosinophil count were recalled for assessment of vasoconstrictor response to topical budesonide. The MacKenzie vasoconstrictor assay was performed by applying tenfold dilutions from 10−2 g/ml to 10−8 g/ml budesonide and visually assessing the degree of skin blanching after 18 h at each concentration. Results. There was a significant overall dose–response effect for the degree of skin blanching at each concentration. There was no significant correlation between the effects on the skin and measures of anti-asthmatic efficacy or systemic effect after 3 weeks of 400 μg/day inhaled budesonide. There was a significant correlation with the overall dose–cutaneous response effect versus the overall dose–response effect with adenosine monophosphate (r=−0.53) but not methacholine bronchial challenge testing or serum cortisol. Conclusion. It may not be possible to use the McKenzie vasoconstrictor assay to predict which patients are most or least susceptible to inhaled corticosteroids for anti-asthmatic efficacy or systemic adverse effects.

Keywords: Skin vasoconstrictor assay Budesonide Asthma

Intrarectal pharmacokinetics of two formulations of quinine in children with falciparum malaria by H. Barennes; H. Sterlingot; N. Nagot; H. Meda; M. Kaboré; M. Sanou; B. Nacro; P. Bourée; E. Pussard (pp. 649-652).
Objective. To compare the intrarectal bioavailabilities of two parenteral formulations of quinine most available in French- (Cinchona alkaloid mixture) and English (hydrochloride salt) -speaking areas of Africa. Methods. The pharmacokinetics of quinine was investigated in four groups of 12 children with acute Plasmodium falciparum malaria receiving 8 mg/kg quinine base every 8 h either as hydrochloride salt or Cinchona alkaloid mixture by a slow 4-h intravenous infusion or intrarectal administration. Body temperature and parasitaemia were monitored, and blood quinine concentrations were measured by means of high-performance liquid chromatography. Results. At 72 h, all the children were aparasitaemic and apyretic. Quinine Cmax values were higher after intravenous infusion of the hydrochloride salt and Cinchona alkaloid mixture (6.9±1.9 µg/ml and 5.2±1.3 µg/ml) than after intrarectal administration (3.5±1.4 µg/ml and 3.1±1.6 µg/ml), but tmax values were similar (3.6±1.5, 4.2±1.0, 4.0±1.9, and 4.7±2.0 h, respectively). Intrarectal relative bioavailabilities of hydrochloride salt solution (57%) and Cinchona alkaloid mixture (62%) were similar. Conclusion. Whatever the parenteral formulation of quinine, the blood concentration–time profiles of quinine were similar after intrarectal administration. Intrarectal administration of hydrochloride salt solution is a possible mode of quinine delivery in remote rural areas of Africa.

Keywords: Quinine hydrochloride salt Cinchona alkaloid mixture Intrarectal administration Pharmacokinetics Childhood malaria

Effect of ciprofloxacin on the pharmacokinetics of ropivacaine by Mika J. Jokinen; Klaus T. Olkkola; Jouni Ahonen; Pertti J. Neuvonen (pp. 653-657).
Objective. To assess the effect of ciprofloxacin on the pharmacokinetics of ropivacaine. Methods. In a double-blind, randomised, cross-over study, nine healthy volunteers were treated for 2.5 days with 500 mg oral ciprofloxacin or placebo twice daily. On day 3, they received a single dose of 0.6 mg/kg ropivacaine intravenously over 30 min. Ropivacaine, 3-hydroxyropivacaine (3-OH-ropivacaine), and (S)-2′,6′-pipecoloxylidide (PPX) in venous plasma and urine were measured for up to 12 h and 24 h, respectively. Results. Ciprofloxacin decreased the mean clearance (CL) of ropivacaine by 31% (P<0.05), with a considerable inter-individual variation (range from −52% to +39%). It also decreased the area under the plasma concentration–time curve (AUC) of 3-OH-ropivacaine by 38% (P<0.05) and urinary excretion of 3-OH-ropivacaine by 27% (P<0.05). Ciprofloxacin increased the AUC of PPX by 71% (P<0.01) and urinary excretion of PPX by 97% (P<0.01). Conclusion. Ciprofloxacin modestly decreased the mean ropivacaine CL by inhibiting the CYP1A2-mediated formation of 3-OH-ropivacaine. At the same time, the CYP3A4-mediated formation of PPX was increased. There was a marked inter-individual variation in the extent of the interaction, and, for some individuals, the concomitant use of ciprofloxacin with ropivacaine might produce toxic symptoms.

Keywords: Drug interaction Ropivacaine Ciprofloxacin

CYP2D6*10 alleles do not determine plasma fluvoxamine concentration/dose ratio in Japanese subjects by Koichi Ohara; Shigeru Tanabu; Kazuhisa Ishibashi; Keiko Ikemoto; Kimiko Yoshida; Haruo Shibuya (pp. 659-661).
Abstract Objective. The purpose of the present study was to investigate whether plasma fluvoxamine (FV) concentration is associated with CYP2D6*10 allele polymorphisms. Methods. Subjects were 46 Japanese patients (21 males) carrying neither *3, *4 nor *5 alleles and treated orally using FV. Venous blood was obtained from each patient for determination of FV concentration/dose (C/D) ratio (plasma concentration of FV divided by daily dose of FV per body weight) and CYP2D6 genotyping. Results. No significant differences in FV C/D ratio were found between subjects with no (n=13), one (n=18) or two (n=15) *10 alleles. Conclusion. Our results indicate that CYP2D6*10 genotypes do not exert significant effects on FV C/D ratio. As CYP2D6 genotypes differ with ethnic background, further studies should be conducted in different populations.

Keywords: Fluvoxamine CYP2D6 *10 allele

Identification of epoxybergamottin as a CYP3A4 inhibitor in grapefruit peel by H. Wangensteen; E. Molden; H. Christensen; K. E. Malterud (pp. 663-668).
Objective. The oral availability of many drugs metabolised by the enzyme cytochrome P 450 3A4 (CYP3A4) is increased if co-administered with grapefruit juice. Extracts from grapefruit peel have also demonstrated inhibitory activity and, during commercial manufacturing of grapefruit juice, inhibitory components might be squeezed into the juice from the peel. Thus, the aim of this in vitro study was to identify CYP3A4 inhibitors in grapefruit peel. Methods. Grapefruit peel was extracted with diethyl ether, and the extract was further fractionated by normal-phase chromatography. Fractions demonstrating significant CYP3A4 inhibitory activity, as measured by the relative reduction in N-demethylation of diltiazem in transfected human liver epithelial cells, were subsequently separated by preparative thin-layer chromatography. Constituents of the fractions and isolated compounds were identified by nuclear magnetic resonance spectroscopy. Analysis of diltiazem and N-demethyl-diltiazem was performed using high-performance liquid chromatography. Results. Of the identified components in grapefruit peel, only epoxybergamottin demonstrated a concentration-dependent inhibition of the CYP3A4-mediated N-demethylation of diltiazem. The IC50 value was calculated to be 4.2±1.1 µM. Coumarins without the furan ring and flavonoids isolated from grapefruit peel did not interfere with the metabolism of diltiazem. The results indicated the presence of other CYP3A4 inhibitors in grapefruit peel, but these agents were lost during the purification process excluding their identification. Conclusion. The furanocoumarin epoxybergamottin, present in grapefruit peel, is an inhibitor of CYP3A4. In commercial manufacturing of grapefruit juice, epoxybergamottin is possibly distributed into the juice. During manufacturing, however, epoxybergamottin may be hydrolysed to 6´,7´-dihydroxybergamottin, which has been suggested as an important CYP3A4 inhibitor in grapefruit juice.

Keywords: Grapefruit peel Furanocoumarins Epoxybergamottin

Pharmacokinetics and pharmacodynamics of rosuvastatin in subjects with hepatic impairment by S. G. Simonson; P. D. Martin; P. Mitchell; D. W. Schneck; K. C. Lasseter; M. J. Warwick (pp. 669-675).
Objective. To assess the effect of chronic hepatic impairment on rosuvastatin disposition, pharmacodynamic activity and tolerability. Methods. This was an open-label, non-randomised, parallel-group trial. Six subjects were enrolled in each of three hepatic-function strata: Child-Pugh class A (CP-A, mild impairment), Child-Pugh class B (CP-B, moderate impairment) and normal hepatic function; the latter two strata were age, weight, race, sex and smoking history matched. All subjects were given rosuvastatin 10 mg for 14 days. Results. In subjects with CP-A, and in four of six subjects with CP-B, rosuvastatin steady-state AUC(0–24) and Cmax were similar to subjects with normal hepatic function (geometric mean values 60.7 ng h/ml and 6.02 ng/ml, respectively). Two of six subjects with CP-B who had the highest CP scores (i.e. the highest degrees of hepatic impairment) had the highest AUC(0–24) (128 ng h/ml and 242 ng h/ml) and Cmax (23.4 ng/ml and 96.7 ng/ml) values. Low-density lipoprotein cholesterol (LDL-C) was decreased in all strata, but the response was more variable in the CP-B group. Rosuvastatin was well tolerated, and the safety profile was similar in subjects with hepatic impairment and normal hepatic function. Conclusion. In most subjects with mild-to-moderate hepatic impairment, the steady-state pharmacokinetics of rosuvastatin were similar to subjects with normal hepatic function (more extensive hepatic impairment may increase systemic exposure to rosuvastatin), and most had LDL-C reductions similar to subjects with normal hepatic function.

Keywords: Rosuvastatin HMG-CoA reductase inhibitors Hepatic impairment Pharmacokinetics Pharmacodynamics

Transplacental passage of lamotrigine in a human placental perfusion system in vitro and in maternal and cord blood in vivo by Päivi K. Myllynen; Päivi K. Pienimäki; Kirsi H. Vähäkangas (pp. 677-682).
Objective. We studied transplacental passage of lamotrigine (3,5-diamino-6-[2,3-dichlorophenyl]-1,2,4-triazine; LTG) using an ex vivo human placental perfusion method and in in vivo samples. Methods. Term placentas from healthy mothers without medications were perfused in a recirculating dual perfusion system. LTG (2.5 μg/ml, n=4; 10 μg/ml, n=4) and reference compound antipyrine (100 μg/ml) were added into the maternal circulation. The disappearance of drugs from the maternal circulation and appearance into the foetal circulation was followed every 15 min up to 2 h. Drug concentrations were analysed using high-performance liquid chromatography. In addition to human placental perfusions, we analysed LTG concentrations in maternal vein and cord blood samples after delivery from two epileptic mothers receiving LTG therapy during pregnancy. Results. LTG was detectable in the foetal circulation at 15 min in all of the perfusions, indicating rapid transfer. Maternal and foetal concentrations reached equilibrium at 60 min with both concentrations used. The feto–maternal ratio was 1.26±0.20 with 10 μg/ml LTG and 0.83±0.41 with 2.5 μg/ml LTG at the end of the perfusion. The transfer of LTG from the maternal to the foetal compartment at 120 min was 28.9±10.7% with 2.5 μg/ml LTG and 37.8±3.2% with 10 μg/ml LTG (p>0.05). In the serum samples from epileptic mothers, the cord blood maternal concentration ratio was 1.02 in one pair and 1.55 in the other. Conclusions. LTG crossed the placenta easily and rapidly, indicating that the maternal treatment leads to a considerable foetal exposure.

Keywords: Lamotrigine Pregnancy Human placental perfusion

A clinical study investigating the pharmacokinetic interaction between NN703 (tabimorelin), a potential inhibitor of CYP3A4 activity, and midazolam, a CYP3A4 substrate by Milan Zdravkovic; Anette K. Olsen; Tina Christiansen; Rainer Schulz; Mitchell E. Taub; Mikael S. Thomsen; Michael H. Rasmussen; Mapoko M. Ilondo (pp. 683-688).
Objective. NN703 (tabimorelin) is an orally active growth hormone (GH) secretagogue intended for use as an alternative to daily injections of GH. In vitro studies in human liver microsomes have indicated that NN703 is a mechanism-based inhibitor of CYP3A4. The aim of the present study was to investigate in man the effects of NN703 on the pharmacokinetics of midazolam, a substrate of CYP3A4. Methods. Seventeen adult male subjects were enrolled in the study, and each received an oral dose of midazolam (7.5 mg) on four occasions: at baseline (day 1), after one dose of NN703 (day 3), after 7 days once daily NN703 treatment (day 9) and after a 7-day washout period (day 16). The pharmacokinetics of midazolam and its main metabolite, α-hydroxymidazolam, were investigated. Results. Following a single dose of NN703 (day 3), the AUC of both midazolam and α-hydroxymidazolam increased by 64% and 34%, respectively (P=0.0001 for both). After repeated NN703 dosing (day 9), NN703 levels reached steady state, and midazolam AUC further increased to 93% relative to baseline (P=0.0001), whereas α-hydroxymidazolam AUC decreased slightly and was 11% higher than baseline (n.s.). Following the washout period (day 16), midazolam AUC decreased to values lower than those on day 3 and day 9, but still significantly (45%) higher than baseline levels (P=0.0001). The Cmax values of midazolam and α-hydroxymidazolam demonstrated a pattern similar to the AUC, but the effect following repeated NN703 dosing was more pronounced. The t1/2 of midazolam increased from day 1 to day 3 (P=0.0483) but was essentially unchanged at steady state on day 9. Conclusion. This study shows that administration of NN703 and midazolam, a CYP3A4 substrate, leads to a significant increase in exposure of midazolam. This is consistent with NN703 inhibition of CYP3A4 activity.

Keywords: CYP3A4 Interaction Midazolam NN703 Clinical study

Initial 3-month usage characteristics predict long-term use of benzodiazepines: an 8-year follow-up by Rolf van Hulten; K. Bart Teeuw; Albert Bakker; Hubert G. Leufkens (pp. 689-694).
Objective. The aim of the study was to identify initial usage predictors for prolonged benzodiazepine use. Methods. An 8-year pharmacy data-based study (1983–1992) was carried out on a retrospective cohort of 425 initial benzodiazepine users. The setting was the only pharmacy in a community of 13,500 people. Results. Among the 425 initial users, 36% had a single initial exposure year, 50% had two to seven exposure years, and 14% had benzodiazepine use during all 8 years of follow-up. Prolonged use over more years was associated with an initial high number of prescriptions, elderly patients and initial use of hypnotics. Two patterns of irregular prolonged use were investigated: increase in use was associated with a shorter length of the first usage period and switching to another benodiazepine during the first 90 days; relapses of use were associated with a shorter length of first usage period and initial use of an anxiolytic. Gender and initial dosage were not associated with prolonged use at all. Conclusion. During the first 90 days after initiation of benzodiazepine use, a number of determinants of prolonged benzodiazepine use were visible. The prescribers of these drugs and the pharmacists should advise rational use not only at the start but also at the moment of the first repeat prescription in order to prevent needless prolonged use and dependence.

Keywords: Benzodiazepines Long-term use General population

Use of calcium antagonists and worsening renal function in patients receiving angiotensin-converting-enzyme inhibitors by Giuseppe Zuccalà; Graziano Onder; Claudio Pedone; Matteo Cesari; Emanuele Marzetti; Alberto Cocchi; Pierugo Carbonin; Roberto Bernabei (pp. 695-699).
Objective: The objective of this study was to assess whether calcium antagonists, which have been proven to dilate the afferent glomerular arteriole, might prevent increases in serum creatinine levels among older subjects who started treatment with angiotensin-converting enzyme (ACE) inhibitors. Methods: We explored the association between use of calcium antagonists and incident increases in serum creatinine in 780 elderly patients with baseline creatinine levels <1.2 mg/dL (106.19 μmol/L), who were enrolled in a multicenter pharmacoepidemiology study, and who started using ACE inhibitors during their hospital stay. Among these participants, 279 also started using calcium antagonists. Demographic variables, comorbid conditions, medications, and objective tests, which were associated with increasing serum creatinine levels in separate regression models, were examined as potential confounders in a summary model. Results: Among patients receiving ACE inhibitors, serum creatinine levels increased in 22% of participants who were dispensed calcium antagonists, and in 31% of other patients (P=0.005). In the summary regression model, use of calcium antagonists was associated with a decreased risk of worsening renal function (RR 0.56, 95% CI 0.37–0.84). The adjusted risk of increasing serum creatinine was lower (RR 0.25, 95% CI 0.05–0.95) in participants receiving higher calcium antagonists dosages than in those taking lower dosages. This protective effect of calcium antagonists was not detected in patients not dispensed ACE inhibitors. Conclusion: ACE inhibitors are underused in older subjects, mainly because of the higher incidence of renal damage among geriatric populations. Our results indicate that among elderly patients receiving ACE inhibitors, the use of calcium antagonists is associated with a reduced risk of worsening renal function. Thus, these results warrant trials aiming at establishing whether combined treatment with calcium antagonists might allow the use of ACE inhibitors in clinical practice to be expanded to the elderly population.

Keywords: Angiotensin-converting enzyme inhibitors Calcium antagonists Renal failure Elderly

Determinants for drug prescribing to children below the minimum licensed age by Geert W. 't Jong; Ingo A. Eland; Miriam C. J. M. Sturkenboom; John N. van den Anker; Bruno H. C. Stricker (pp. 701-705).
Objectives: In the light of the undesired effects that unlicensed and off-label drug use might have, it is necessary to study the determinants affecting the prescribing of such drugs. Prescription of drugs to children younger than the minimum licensed age may carry the highest risk of adverse reactions. To obtain insight into the factors that affect prescription of drugs to children below the minimum licensed age, we conducted a population-based case-control study. Methods: The case-control study was nested in a cohort of 13,426 children aged 0–16 years, who were registered in the Integrated Primary Care Information (IPCI) project, a longitudinal observational general practitioners' database in the Netherlands. "Cases" were children who received a drug prescription for which they were below the minimum licensed age. To each case we matched up to four controls based on GP practice and patient age. As potential risk factors we evaluated the use of health care resources, and acute and chronic morbidity. Results: We identified 447 cases who were matched to 1355 controls. The cases consulted their GPs significantly more often during the preceding half year, had more drug prescriptions, and had more specialist referrals than the controls. Respiratory diseases were the most important determinants for the prescription of drugs to children below the minimum licensed age. In adolescents, migraine and other headaches were the most important reasons. Conclusions: This study showed that children suffering from respiratory disease or migraine have the highest risk of receiving a drug prescription for which the patient is below the minimum licensed age. Regulatory authorities and the pharmaceutical industry should be stimulated to improve the evaluation of drug efficacy and safety in children.

Keywords: Drug use Children Determinants Age restrictions Unlicensed Off-label

Reporting adverse drug reactions on a geriatric ward: a pilot project by Annemie Somers; Mirko Petrovic; Hugo Robays; Marc Bogaert (pp. 707-714).
Abstract Objective. To test a method for registration of adverse drug reactions (ADRs) resulting in hospital admission and of ADRs occurring during hospital stay. Spontaneous reporting was compared with data from patient interview. Methods. Spontaneous reporting of ADRs by nurses and physicians, as well as patient interviews by pharmacists. This pilot project was carried out in the geriatric ward of the Ghent University Hospital over a period of 8 months in order to develop suitable registration forms and to test feasibility. Causality, severity, type and level of intervention of the reported ADRs were analysed. Reports from physicians and nurses were compared with the data obtained by patient interviews. Results. During the 8 months, for 168 patients, 12 spontaneous reports were received from physicians and nurses. Fifty-six of these patients were interviewed and 32 ADRs were reported. Only 2 ADRs detected by patient interview were also reported spontaneously. The interviews of the 56 geriatric patients indicated that 20% of them were admitted to the hospital because of an ADR. ADRs occurred during hospital stay in another 20% of those patients. Conclusion. Spontaneous reporting by physicians and nurses revealed considerably fewer ADRs than patient interview by pharmacists. Physicians and nurses reported the more serious ADRs that occurred during hospital stay, whereas the interviews revealed more ADRs that caused hospital admission. Our data confirm that ADRs are an important cause of hospital admission of geriatric patients and occur frequently during their hospital stay.

Keywords: Adverse drug events (ADE) Adverse drug reactions (ADR) Patient interview Pharmacovigilance Spontaneous reporting

Raynaud's phenomenon induced by drugs acting on neurotransmission: two cases under reboxetine and one under tegaserod by Raffaela Bertoli; François Girardin; Stefan Russmann; Bernhard H. Lauterburg (pp. 717-717).
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