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The standard treatment for ovarian cancer in advanced stages is post-surgery treatment with taxane-platin chemotherapy. Despite an initial high response rate, most patients eventually relapse. The dose-limiting toxicities of paclitaxel are neutropenia and neuropathy, but the inter-individual variability is large. The aim of this prospective study was to investigate the impact of genetic variants in key drug metabolizing/transporter genes on toxicity and compliance. CYP2C8*3 and three ABCB1 polymorphisms were chosen for primary analysis, and a host of other candidate genes was explored in 92 prospectively recruited Scandinavian Caucasian women with primary ovarian cancer who were treated with paclitaxel and carboplatin. A single investigator assessed the clinical toxicity in 97% of the patients. Patients carrying variant alleles of ABCB1 C3435T experienced more pronounced neutrophil decrease (63%, 72% and 80% for 3435CC, CT and TT, respectively; p-value 0.03). A similar association was found for G2677T/A, p-value 0.02. For C1236T, there was a trend with p-value 0.06. No statistically significant correlations were found for paclitaxel compliance and sensory neuropathy in the primary analysis. Variants in the drug transporter ABCB1 gene are possibly associated with the neutrophil suppressing effect of paclitaxel in patients with ovarian cancer. This finding has implications for the understanding of bone marrow suppression and future tailored chemotherapy.

The primary purpose of this study was to evaluate the effect of CYP2C8*3 and three genetic ABCB1 variants on the elimination of paclitaxel. We studied 93 Caucasian women with ovarian cancer treated with paclitaxel and carboplatin. Using sparse sampling and nonlinear mixed effects modeling, the individual clearance of unbound paclitaxel was estimated from total plasma paclitaxel and Cremophor EL. The geometric mean of clearance was 385 l h(-1) (range 176-726 l h(-1)). Carriers of CYP2C8*3 had 11% lower clearance than non-carriers, P = 0.03. This has not been shown before in similar studies; the explanation is probably the advantage of using both unbound paclitaxel clearance and a population of patients of same gender. No significant association was found for the ABCB1 variants C1236T, G2677T/A and C3435T. Secondarily, other candidate single-nucleotide polymorphisms were explored with possible associations found for CYP2C8*4 (P = 0.04) and ABCC1 g.7356253C andgt; G (P = 0.04). Original Publication:T K Bergmann, C Brasch-Andersen, Henrik Green, M Mirza, R S Pedersen, F Nielsen, K Skougaard, J Wihl, N Keldsen, P Damkier, L E Friberg, Curt Peterson, W Vach, M O Karlsson and K Brosen, Impact of CYP2C8*3 on paclitaxel clearance: a population pharmacokinetic and pharmacogenomic study in 93 patients with ovarian cancer, 2011, PHARMACOGENOMICS JOURNAL, (11), 2, 113-120.http://dx.doi.org/10.1038/tpj.2010.19Copyright: Nature Publishing Grouphttp://npg.nature.com/

I appreciate the review on the ongoing controversial subject of tamoxifen treatment of post-menopausal breast cancer and CYP2D6 genotyping by Brauch & Schwab [1]. However, I am somewhat surprised that on at least two central issues the authors do not discuss original findings that fail to support their position. While I do not claim that there is no issue with tumour-line derived genotyping as opposed to germ-line genotyping, at least two different studies have been published that suggest a high degree of concordance [2,3]. I believe such data and positions warrant discussion in the context of the present review. On the issue of concomitant treatment with tamoxifen and CYP2D6 inhibitors for support of the biological rationale as suggested by the authors, one study demonstrated an effect of paroxetine, but an interaction effect could not be demonstrated for fluoxetine, a very potent and effective inhibitor of CYP2D6 [4]. Another study did not confirm an interaction between CYP2D6 inhibitors and breast cancer recurrence in tamoxifen treated patients [5]. Additionally, despite the determined opinion of the authors on the Hardy–Weinberg equilibrium (HWE) issue as related to various clinical sets of data, this may not be as clear as they would like it to be [6,7]. In fact, the publication highlighted by the authors for credibility on this matter [8], itself contains a sample violating the HWE [9]. Despite the authors' introductory acknowledgement of an ongoing controversy, the uninitiated reader is left with the impression that the pro et contra of CYP2D6 genotyping prior to tamoxifen treatment in postmenopausal breast cancer, is now settled once and for all in favour of the pro. The conclusion of the meta-analysis recently published by the International Tamoxifen Pharmacogenomics Consortium [10], to which the two authors themselves belong, appears more balanced.

Paclitaxel has a broad spectrum of anti-tumor activity and is useful in the treatment of ovarian, breast, and lung cancer. Paclitaxel is metabolized in the liver by CYP2C8 and CYP3A4 and transported by P-glycoprotein. The dose-limiting toxicities are neuropathy and neutropenia, but the interindividual variability in toxicity and also survival is large. The main purpose of this study was to investigate the impact of genetic variants in CYP2C8 and ABCB1 on toxicity and survival.The 182 patients previously treated for ovarian cancer with carboplatin and paclitaxel in either the AGO-OVAR-9 or the NSGO-OC9804 trial in Denmark or Sweden were eligible for this study. Genotyping was carried out on formalin-fixed tissue. The patients' toxicity profiles and survival data were derived from retrospective data. CYP2C8*3, ABCB1 C1236T, G2677T/A, and C3435T were chosen a priori for primary analysis; a host of other variants were entered into an exploratory analysis.Clinical data and tissue were available from a total of 119 patients. Twenty-two single nucleotide polymorphisms (SNPs) in 10 genes were determined. Toxicity registration was available from 710 treatment cycles. In the primary analysis, no statistically significant correlation was found between CYP2C8*3, ABCB1 C1236T, G2677T/A, and C3435T and neutropenia, sensoric neuropathy, and overall survival.CYP2C8*3 and the ABCB1 SNPs C1236T, G2677T/A, and C3435T were not statistically significantly correlated to overall survival, sensoric neuropathy, and neutropenia in 119 patients treated for ovarian cancer with paclitaxel/carboplatin.

PURPOSE: To investigate paroxetine's putative dose-dependent impact on pupil reaction and inhibition of the O-demethylation of tramadol.METHODS: Twelve healthy CYP2D6 extensive metabolizers participated in this double-blinded randomized five-way placebo controlled cross-over study; they received placebo, 10, 20, 30, and 50 mg paroxetine as single oral doses at bedtime. Next morning the pupil was measured followed by oral intake of 50 mg of tramadol, and urine was collected for 8 h. Three hours after ingestion of tramadol a second measurement of the pupil was performed. Enantioselective urine concentrations of (+/-)-tramadol and (+/-)-O-desmethyltramadol (M1) were determined.RESULTS: With placebo, the median maximum pupil diameter was 6.43 mm (range 5.45-7.75 mm) before tramadol and 6.22 mm (4.35-7.65 mm) after 50 mg of tramadol (P = 0.4935). Paroxetine resulted in a statistically significant, dose-dependent dilatation of the pupil with a geometric mean difference of 1.17 (95% CI 1.10-1.24) after ingestion of 50 mg paroxetine (P < 0.001). Likewise, a reduction in the relative constriction amplitude with a geometric mean difference of 0.81 (95% CI 0.71-0.92) (P < 0.001) was seen. A dose-dependent inhibition of the metabolism of tramadol by an increase in the two urinary metabolic ratios (+)-tramadol / (+)-M1 [geometric mean difference 9.09, 95% CI 5.60-14.73 (P < 0.001)] and (-)-M1 / (+)-M1 [geometric mean difference 2.84, 95% CI 2.15-3.77 (P < 0.001)] was also observed.CONCLUSIONS: Paroxetine is a dose-dependent dilator of the pupil and as expected a dose-dependent inhibitor of (+)-tramadol's O-demethylation.

Tramadol is O-demethylated to the active metabolite (+)-O-desmethyltramadol ((+)-M1) via CYP2D6, an enzyme that is weakly inhibited by escitalopram. We investigated the possibility of a pharmacokinetic (PK) and pharmacodynamic (PD) effect of escitalopram on tramadol metabolism. Fifteen healthy subjects completed this randomized, double-blind, three-phase, crossover trial. Combinations of escitalopram 20 mg/day or placebo together with tramadol 150 mg or placebo were used. Blood samples for pharmacokinetics were drawn at 0-24 h after medication. The analgesic effect of (+)-M was assessed by the cold pressor test (CPT) (area under effect curve, 1-12 h after medication (AUEC(1-12))). The median area under plasma concentration-time curve extrapolated to infinity (AUC(0-infinity)) of (+)-M1 was 2.75 micromol/l.h after placebo pretreatment compared with 1.95 micromol/l.h after escitalopram (P = 0.0027). The mean AUEC(1-12) of CPT were 4,140 and 4,388 cm.s after placebo and escitalopram, respectively (P = 0.71). Although escitalopram is a weak inhibitor of CYP2D6, it does not impair the analgesic effect of tramadol.

Udgivelsesdato: 2009-Jun BACKGROUND: Clinical and epidemiological studies have associated selective COX-2 inhibitors with an increased risk of cardiovascular events. There are no clinical studies on the possible effects of these drugs on secondary hemostasis. The hypothesis for this study is that the use of selective COX-2 inhibitors could affect the secondary hemostasis and by that increase the risk of cardiovascular events in a population at high risk. METHODS: An open-label randomized cross-over study was performed in 20 healthy male volunteers. The study consisted of two periods of each 21 days with medication, either celecoxib 100 mg b.i.d. or naproxen 250 mg b.i.d. Treatment periods were separated by a washout period of 28 days. Blood samples were obtained before the first medication period, and at the end of each medication period. Primary effect parameter was FXII level. Secondary effect parameters included a wide range of coagulation factors involved in secondary hemostasis. RESULTS: There was no statistically significant effect of celecoxib or naproxen on the primary effect parameter. Protein C activity was significantly decreased after treatment with naproxen (P

PURPOSE: To investigate the impact of cytochrome P450 2C19 (CYP2C19) phenotypes on escitalopram metabolism and to evaluate pupillometry as a serotonergic biomarker. METHODS: This was a double-blind, crossover design study with single and multiple doses of 10 mg escitalopram and placebo in panels of CYP2C19 extensive (EM) and poor metabolisers (PM). Pupillometry was measured by a NeurOptics Pupillometer-PLR. RESULTS: Five PM and eight EM completed the study. The CYP2C19 phenotype significantly affected the metabolism of escitalopram. The area under the time-plasma concentration curve (AUC(0-24)) was 1.8-fold higher in PM than in EM after both single and multiple doses. Escitalopram treatment did not affect the maximum pupil size, but it did statistically significantly decrease the relative amplitude of the pupil light reflex compared to the placebo; this effect was equal in both phenotype groups. CONCLUSIONS: The CYP2C19 polymorphism affects escitalopram metabolism, but the difference does not justify dose adjustment. The puzzling results from pupillometry can be due to interplay between a central and a local serotonergic effect. Based on these results, pupillometry can not be recommended as a serotonergic biomarker.

Problem-oriented drug information (POD) is a service in which health professionals provide evidence-based answers to clinical questions posed by physicians. The objective of this study was to evaluate the user satisfaction and clinical impact of POD, to investigate predictors for use and to examine the kind of sources physicians search before applying for POD. To evaluate POD, a questionnaire was distributed with problem-oriented answers sent from a drug information centre to physicians during the period of April 2006 to March 2007. Of 197 questionnaires, 183 (93%) were returned. The information from the POD service was highly valued by the physicians, and 90% of the answers led to reported impact on clinical practice in the specific clinical situation. Furthermore, 74% of the answers were intended to be used in a wider context either for future patients (67%) or for dissemination to colleagues (51%). Secondary-care physicians more often than general practitioners (GPs) used the information for dissemination to colleagues (63 vs. 39%, P = 0.0008), while GPs more often used the answer to support patient information (88 vs. 70%, P = 0.0029). The most prominent motive for applying for POD was a request for evidence-based information (78%), and the service was used to overcome barriers to practicing evidence-based medicine such as lack of time (36%), skills for searching (26%), and appraising the literature (13%). Before inquiring, 74% of the physicians had tried other information sources; the most frequent sources used were a drug reference (68%) and consulting a colleague (24%). Secondary-care physicians reported fewer barriers than GPs when seeking information, and secondary-care physicians searched other sources more often than GPs before contacting the service (81 vs. 67%, P = 0.031). POD represents a useful source for acquiring evidence-based drug information by physicians. POD is highly valued by the users. It was reported to have an impact on clinical practice for the specific patient but is also intended to be used in a wider context for future patients or for dissemination to colleagues. GPs’ and secondary-care physicians’ use of POD differs with GPs having more focus on patient information and secondary-care physicians having more focus on dissemination of the information to colleagues.

In Denmark chlorobutanol-caffeine rectal suppositories are prescribed by some obstetric departments for the treatment of hyperemesis gravidarum.We have investigated the extent of this use by questionnaire, and we have performed a literature review on the evidence of efficacy and safety.The use of chlorobutanol-caffeine rectal suppositories was reported by 5 out of 28 obstetric departments in Denmark. The literature search revealed that there is very sparse information on chlorobutanol. No evidence was found of safety during pregnancy in humans or efficiency as antiemetic treatment in hyperemesis gravidarum.There is no evidence of the efficacy or safety of chlorobutanol-caffeine suppositories for the treatment of hyperemesis gravidarum.

Udgivelsesdato: 2007-May-28 INTRODUCTION: In Denmark chlorobutanol-caffeine rectal suppositories are prescribed by some obstetric departments for the treatment of hyperemesis gravidarum. MATERIALS AND METHODS: We have investigated the extent of this use by questionnaire, and we have performed a literature review on the evidence of efficacy and safety. RESULTS: The use of chlorobutanol-caffeine rectal suppositories was reported by 5 out of 28 obstetric departments in Denmark. The literature search revealed that there is very sparse information on chlorobutanol. No evidence was found of safety during pregnancy in humans or efficiency as antiemetic treatment in hyperemesis gravidarum. CONCLUSION: There is no evidence of the efficacy or safety of chlorobutanol-caffeine suppositories for the treatment of hyperemesis gravidarum.

Udgivelsesdato: 2007-Oct-15 The CYP3A4 enzyme is, along with other cytochrome P450 enzymes, involved in the metabolism of environmental pollutants and is highly inducible by these substances. A commercial polychlorinated biphenyl (PCB) mixture, 1,1,1,-trichloro-2-(o-chlorophenyl), 2-(p'-chlorophenyl)ethane (o,p'-DDT) and 1,1,-dichloro-2,2-bis (p-chlorophenyl)ethene (p,p'-DDE) are known to induce CYP3A4 activity through activation of nuclear receptors, such as the pregnane X receptor. However, this induction of CYP3A4 has not yet been investigated in humans. Thus, the aim of the study was to determine the variability of the CYP3A4 phenotype in regard to increased concentrations of PCBs and other persistent organohalogen pollutants (POPs) in healthy Faroese adults. In 310 randomly selected Faroese residents aged 18-60 years, the CYP3A4 activity was determined based on the urinary 6beta-hydroxycortisol/cortisol (6beta-OHC/FC) ratio. POP exposures were assessed by measuring their concentrations in serum lipid. The results showed a unimodal distribution of the 6beta-OHC/FC ratio with values ranging from 0.58 to 27.38. Women had a slightly higher 6beta-OHC/FC ratio than men (p=0.07). Confounder-adjusted multiple regression analysis showed significant associations between 6beta-OHC/FC ratios and summation PCB, PCB-TEQ and p,p'-DDE, o,p'-DDT and HCB, respectively, but the associations were statistically significant for men only.

Medical treatment of depression during pregnancy and breastfeeding often involves concern by both the patient and the doctor because of the fear of adverse reactions or malformations of the child. This article gives an updated review on how antidepressants, lithium, antipsychotics and ECT can be used during pregnancy and breastfeeding, and presents a treatment algorithm which is used at Odense University Hospital.

Udgivelsesdato: 2007-Apr-16 Medical treatment of depression during pregnancy and breastfeeding often involves concern by both the patient and the doctor because of the fear of adverse reactions or malformations of the child. This article gives an updated review on how antidepressants, lithium, antipsychotics and ECT can be used during pregnancy and breastfeeding, and presents a treatment algorithm which is used at Odense University Hospital.

Udgivelsesdato: 2007-Mar PURPOSE: Carbamazepine (CBZ) and oxcarbazepine (OXCZ) are well-known inducers of drug metabolism via CYP3A4. Indirect interaction studies and clinical experience suggest that CBZ has a stronger potential in this regard than OXCZ. However this has never been subject to a direct comparative study. We performed a study in healthy volunteers to investigate the relative inductive effect of CBZ and OXCZ on CYP3A4 activity using the metabolism of quinidine as a biomarker reaction. METHODS: Ten healthy, male volunteers participated in an open, randomized crossover study consisting of two periods separated by a 4-week wash-out period. The subjects received 1200 mg oral OXCZ daily for 17 days and 800 mg oral CBZ for 17 days. A single 200 mg oral dose of quinidine was administered at baseline and following administration of CBZ and OXCZ. Outcome parameters were the formation clearance of 3-hydroxyquinidine dose and the ratio of the AUCs of 3-hydroxyquinidine to quinidine. RESULTS: Formation clearance of 3-hydroxyquinidine was increased by means of 89% (CI: 36-164; p=0.0022) and 181% (CI: 120-260, p

AIMS: To determine the effect of CYP2C8 genotype and of fluvoxamine on the pharmacokinetics of rosiglitazone.METHODS: Twenty-three healthy subjects with the following genotypes were included in a two-phase, open-label, cross-over trial: CYP2C8*3/ *3 (n = 3), CYP2C8*1/ *3 (n = 10) and CYP2C8*1/ *1 (n = 10). In Phase A, the subjects were given 4 mg rosiglitazone as a single oral dose. In Phase B, the subjects were treated with multiple oral doses of 50 mg fluvoxamine maleate for 3 days prior to the single oral administration of 4 mg rosiglitazone. Plasma concentrations of rosiglitazone and relative amounts of N-desmethylrosiglitazone were measured in both phases for 24 h after drug administration.RESULTS: The pharmacokinetics of rosiglitazone and N-desmethylrosiglitazone were not significantly different between the CYP2C8 genotypic groups. Fluvoxamine caused a statistically significant (P = 0.0066) increase in the AUC(0-infinity) of rosiglitazone, with a geometric mean ratio of 1.21 [95% confidence interval (CI) 1.06-1.39]. The elimination half-life (t(1/2)) was also significantly higher (P = 0.0203) with a geometric mean ratio of 1.38 [95% CI 1.06-1.79]. The coadministration of fluvoxamine had no influence on the pharmacokinetics of N-desmethylrosiglitazone.CONCLUSION: The importance of the CYP2C8*3 mutation in the in vivo metabolism of rosiglitazone could not be confirmed. Fluvoxamine increased the AUC(0-infinity) and t(1/2) of rosiglitazone moderately and hence may be a weak inhibitor of CYP2C8.

Aims The primary aim of the study was to investigate the possible effect of the CYP2C8*3 allele and of grapefruit juice on the pharmacokinetics of repaglinide. Furthermore, the impact of a single dose of grapefruit juice on the pharmacokinetics of repaglinide in relation to dose. Methods Thirty-six healthy male subjects, genotyped for CYP2C8*3 (11 genotyped as CYP2C8*1/*3, one as CYP2C8*3/*3 and 24 as CYP2C8*1/*1), participated in a randomized, cross-over trial. In the two phases, the subjects drank 300 mL water or 300 mL grapefruit juice, in randomized order, 2 h before administration of a single dose of either 0.25 mg or 2 mg repaglinide. Results Neither the mean AUC0−∞ (geometric mean ratio: 1.01; 95% CI: 0.93–1.1, P = 0.88) nor the mean Cmax (geometric mean ratio: 1.05; 95% CI: 0.94–1.2, P = 0.35) of repaglinide were statistically significantly different in the group carrying the CYP2C8*3 mutant allele compared with wild-types. Grapefruit juice caused a 19% decrease in the geometric mean ratio of the 3-hydroxyquinidine to quinidine ratio (difference: 0.81; 95% CI: 0.75–0.87, P

SummaryRecent studies suggest that cytochrome P450 (CYP) 3A4 metabolized statins attenuate the antiaggregatory effect of clopidogrel. We evaluated how CYP3A4 metabolized statins and non- CYP3A4 metabolized statins influence platelet aggregation when given concomitantly with clopidogrel. Sixty-six stable patients with ischemic heart disease were included in this parallel group study. All patients were on clopidogrel and aspirin. Thirty-three patients received a CYP3A4 metabolized statin (simvastatin or atorvastatin), and 33 were treated with a non- CYP3A4 metabolized statin (pravastatin). The antiplatelet effect of clopidogrel was assessed at inclusion and 21 days after statin discontinuation. Platelet function was evaluated by two methods 1) optical platelet aggregometry after stimulation with 20 and 30 μM ADP, and 2 and 4 mg/l collagen, respectively, 2) a Platelet FunctionAnalyzer-100. The primary effect measure was final platelet aggregation after stimulation with 20 μM ADP. No difference was observed between patients treated with a CYP3A4 metabolized statin and patients receiving a non-CYP3A4 metabolized statin (30% point (7–42) versus 20% point (9–32), p=0.83). Platelet aggregation was not improved by discontinuation of statins for 21 days. Indeed, we found that statin treatment given concomitantly with clopidogrel resulted in an improved platelet inhibition when compared to clopidogrel given alone. The antiplatelet effect of clopidogrel is not attenuated by concomitant treatment with a CYP3A4 metabolized statin in patients with clinical stable ischemic heart disease.

Udgivelsesdato: 2005-Feb Clopidogrel is an inactive prodrug, which requires activation by the cytochrome P450 3A4 system in order to exert its antiplatelet action. Some statins (atorvastatin, lovastatin and simvastatin) also requires metabolism by the cytochrome P450 3A4 system. From a theoretical point of view, a clinical relevant interaction may exist between clopidogrel and cytochrome P450 3A4 metabolized statins. Nine studies have investigated the existence of this potential interaction. Seven studies have used results based on platelet function as surrogate endpoints and two studies have dealt with objective clinical events including mortality, acute myocardial infarction and stroke. However the studies have yielded conflicting results. This controversy is primarily caused by substantial differences in study design and methods used for assessment of the antiaggregatory effect of clopidogrel. Most studies have included too few patients, and there appears to be no consensus regarding the definition of and optimal way of measuring the platelet inhibitory effect of clopidogrel. Therefore an adequately powered prospective study, ensuring elimination of identified possible confounders and with the use of a well-defined surrogate ex vivo parameter should be performed.

The purpose of the study was to study the distribution of poor and extensive metabolizers of CYP2C19 and CYP2D6 and to genotype for CYP2C8 and CYP2C9 among 312 randomly selected Faroese.The participants were phenotyped for CYP2D6 with the use of sparteine. The distribution of the sparteine metabolic ratio (sparteine/didehydrosparteines) was bimodal, and 14.5% (n=44; 95% CI: 10.7--18.9%) of the subjects were phenotyped as poor metabolizers. The frequency of poor metabolizers was higher (P=0.0002; chi(2) test) among the Faroese than in other European populations (7.4%). Genotype analyses for the CYP2D6*3, *4, *6 and *9 alleles were performed using real-time polymerase chain reaction (PCR) (TaqMan, Foster City, CA, USA), and we found 14.6% (n=45) (95% CI: 10.8--19.0%) with deficient CYP2D6 genes (*3/*4, *4/*4, *4/*6, *6/*6) in the Faroese population. The subjects were phenotyped for CYP2C19 with the use of mephenytoin and 10 subjects, i.e., 3.2% (95% CI: 1.6--5.9%) were phenotyped as poor metabolizers. Genotype analysis for the CYP2C19*2 and *3 alleles was performed by means of PCR analysis, and 2.9% (n=9) (95% CI: 1.3-5.4%) of the Faroese were found to have a deficient CYP2C19 gene all explained by the CYP2C19*2/*2 genotype. The allele frequencies of the CYP2C9*2 and CYP2C9*3 alleles were 8.8% (95% CI: 6.7--11.4%) and 5.3% (95% CI: 3.7--7.4%), respectively, while the CYP2C8*3 allele frequency was 6.9% (95% CI: 5.0--9.2%). Real-time PCR (TaqMan) was used for both CYP2C9 and CYP2C8 genotype analyses.The frequency of CYP2D6 poor metabolizers is twofold higher among the Faroese population than other Caucasians, while the frequencies of Faroese subjects with decreased CYP2C19, CYP2C8 and CYP2C9 enzyme activity are the same as seen in other Caucasian populations. A possible consequence might be a higher incidence of side effects among Faroese patients taking pharmaceuticals that are CYP2D6 substrates.

The aim is to emphasize the importance of extracardiac symptoms of digoxin intoxication in newborns. The most common intoxication symptoms in adults are of cardiac origin, but due to altered symptomatology, digoxin overdose in infants are not always discovered on symptomatic basis. In preterm infants, this is even more pronounced due to diminished digoxin sensitivity. Also, tissue distribution is altered in newborns, which, combined with the need for higher doses in newborns to obtain clinical effect, underscores the need for the utmost care, when newborns receive digoxin treatment to avoid intoxication. We report a case of severe digoxin intoxication in a preterm newborn infant, leading to distinct gastrointestinal symptoms, but only minor cardiac affection. The literature concerning digoxin intoxication and digoxin measurement is reviewed to elucidate the case report. In conclusion, alertness should be drawn to extracardiac symptoms of digoxin intoxication, especially in newborns, and P-Potassium can serve as a predictor and thereby strengthen any given suspicion. Therapeutic drug monitoring should be performed, as soon as digoxin overdose due to the above- mentioned signs is suspected in spite of vague cardiac symptoms.

Udgivelsesdato: 2004-Jun-7

To investigate if rifampicin is both an inducer and an inhibitor of repaglinide metabolism, it was determined whether the timing of rifampicin co-administration influences the pharmacokinetics of repaglinide.Male volunteers ( n=12) participated in a randomised, two-period, crossover trial evaluating the effect of multiple doses of 600 mg rifampicin once daily for 7 days on repaglinide metabolism. Subjects were, after baseline measurements of repaglinide pharmacokinetics, randomised to receive, on either day 7 or day 8 of the rifampicin administration period, a single dose of 4 mg repaglinide and vice versa in the following period.When repaglinide was given, together with the last rifampicin dose, on day 7, an almost 50% reduction of the median repaglinide area under the plasma concentration-time curve (AUC) was observed. Neither the peak plasma concentration (C(max)), time to reach C(max) (t(max)) nor terminal half-life (t(1/2)) was statistically significantly affected. When repaglinide was given on day 8, 24 h after the last rifampicin dose, an almost 80% reduction of the median repaglinide AUC was observed. The median C(max) was now statistically significantly reduced from 35 ng/ml to 7.5 ng/ml. Neither t(max) nor t(1/2) was significantly affected.When rifampicin and repaglinide are administered concomitantly, rifampicin seems to act as both an inducer and an inhibitor of the metabolism of repaglinide. After discontinuing rifampicin administration, while the inductive effect on CYP3A4 and probably also CYP2C8 is still present, an even more marked reduction in the plasma concentration of repaglinide was observed. Our results suggest that concomitant administration of rifampicin and repaglinide may cause a clinically relevant decrease in the glucose-lowering effect of repaglinide, in particular when rifampicin treatment is discontinued or if the drugs are not administered simultaneously or within a few hours of each other.

To the Editor: I would like to comment on the recent editorial by Serebruany et al1 in which the study results by Lau et al2 are discussed. It is argued that these results, which are suggestive of a clinically relevant interaction between clopidogrel and atorvastatin, are in conflict with those published previously by Serebruany et al.3 According to the editorial,1 “…only …

I appreciate the paper by Bolea-Alamanac et al. 1 on the use of methylphenidate in pregnancy and lactation. I would like to point the interested reader towards another recent review on this subject 2. We documented at least 180 first trimester exposed cases (excluding case stories and the case series referred to by Bolea-Alamanac et al. as this series was confounded by intravenous abuse of methylphenidate and concomitant use of pentazocine). We did not find that first trimester in utero exposure to methylphenidate was associated with an increased risk of congenital malformations.

The aim of the study was to determine the death rate and the risk of developing colorectal cancer in patients with ulcerative colitis in Funen County.The medical records of 801 patients with ulcerative colitis diagnosed in 1973-93 in Funen County were scrutinized with regard to colectomy, survival, and colorectal cancer, and in 1998 a follow-up was carried out.The patients were managed at nine different hospitals: one university hospital, one central hospital, and seven smaller hospitals. The mean age at diagnosis was 41 years, and the mean duration of disease was 10.11 years. Sixty-one per cent of the patients were classified as having proctosigmoiditis, 21% as having left-sided colitis, and 18% as having pancolitis. In 127 patients who underwent proctocolectomy during the study period lethal complications occurred in 8 cases: 5 of 110 in Odense University hospital and 3 of 17 in the other hospitals. One hundred and twenty patients in the cohort died during the period of observation, nine of them of colitis-related causes. There was a slightly increased risk of early death in the cohort after 15 years of disease. Six colorectal cancers were found, whereas four were expected, giving a standard incidence ratio of 1.665. The cumulative cancer risk after 20 years' disease duration was 5.3% in the observed group, contrasting with an expected rate of 0.49%, and 10.1% after 25 years.In this cohort of ulcerative colitis patients the mortality and the risk of developing colorectal cancer were slightly higher than expected compared with the background population.

OBJECTIVE: We described incidence rates of esophageal adenocarcinoma in Denmark in a 20-yr period and determined the proportion of patients diagnosed with esophageal adenocarcinoma who had a previous diagnosis of Barrett's esophagus, making them potential candidates for endoscopic surveillance.METHODS: Rates of esophageal and gastric cancers were collected from the Danish Cancer registry for the period 1970-1991. The registry was used to identify all cases of esophageal adenocarcinoma in the period 1987-1992. Medical records were retrieved and details concerning previous diagnosis of reflux disease and Barrett's esophagus were recorded.RESULTS: The age- and gender-adjusted incidence of esophageal adenocarcinoma increased eightfold, from 0.3/10(5)/yr in 1970 to 2.3/10(5)/yr in 1990. This increase could not be explained by changes in classification or diagnostic routines. Medical data were retrieved for 524 of the 578 cases of esophageal adenocarcinoma reported during the period 1987-1992. A history of reflux symptoms or a diagnosis compatible with reflux was reported in 113 of 524 patients. A total of 119 patients (23%) had previously been investigated for dyspepsia or reflux symptoms, most often by endoscopy. A previous diagnosis of Barrett's esophagus was found in only 1.3% of the cancer patients.CONCLUSIONS: The rate of esophageal adenocarcinoma in Denmark has increased eightfold over a 20-yr period, and this increase is not explained by changes in classification or diagnostic routines. More than 98% of esophageal adenocarcinomas were found in patients who could not have entered endoscopic surveillance, as Barrett's esophagus had not been diagnosed before the cancer diagnosis. Endoscopic surveillance to detect dysplasia may be an option for the individual patient with Barrett's esophagus, but these screening programs are not likely to reduce the death rate from esophageal adenocarcinomas in the general population.