Jan Schjøtt

Tamoxifen administration and metabolism in nude mice and nude rats.

We investigated the kinetics of tamoxifen (tam) in immunodeficient mice and rats after oral treatment and compared drug and metabolite profile in nude rat serum and tissues after oral and subcutaneous (s.c.) routes of administration. The serum levels were compared to those observed in man. After oral dosing in mice, tam and the potent metabolite 4-hydroxytamoxifen (4-hydroxytam), were detectable in liver and lung tissue, but not in serum. The levels of 4-hydroxytam in these tissues were significantly higher than those of tam, a profile opposite to that observed in rat and man. In rats and man, the 4-hydroxytam/tam serum concentration ratios were 0.16 and 0.02, respectively. Compared to oral route, the s.c. pellets yielded only trace amounts of the demethylated derivatives of tam in rats. Thus, the kinetics of tam observed in the present study suggest that the nude rat may represent a preferable animal model in studying the pharmacokinetics of tam and that, the oral route yielded higher serum and tissue levels of tam and metabolites than equivalent s.c. pellet implants.

A human clinical trial using ultrasound and microbubbles to enhance gemcitabine treatment of inoperable pancreatic cancer

BACKGROUND The primary aim of our study was to evaluate the safety and potential toxicity of gemcitabine combined with microbubbles under sonication in inoperable pancreatic cancer patients. The secondary aim was to evaluate a novel image-guided microbubble-based therapy, based on commercially available technology, towards improving chemotherapeutic efficacy, preserving patient performance status, and prolonging survival. METHODS Ten patients were enrolled and treated in this Phase I clinical trial. Gemcitabine was infused intravenously over 30min. Subsequently, patients were treated using a commercial clinical ultrasound scanner for 31.5min. SonoVue® was injected intravenously (0.5ml followed by 5ml saline every 3.5min) during the ultrasound treatment with the aim of inducing sonoporation, thus enhancing therapeutic efficacy. RESULTS The combined therapeutic regimen did not induce any additional toxicity or increased frequency of side effects when compared to gemcitabine chemotherapy alone (historical controls). Combination treated patients (n=10) tolerated an increased number of gemcitabine cycles compared with historical controls (n=63 patients; average of 8.3±6.0cycles, versus 13.8±5.6cycles, p=0.008, unpaired t-test). In five patients, the maximum tumour diameter was decreased from the first to last treatment. The median survival in our patients (n=10) was also increased from 8.9months to 17.6months (p=0.011). CONCLUSIONS It is possible to combine ultrasound, microbubbles, and chemotherapy in a clinical setting using commercially available equipment with no additional toxicities. This combined treatment may improve the clinical efficacy of gemcitabine, prolong the quality of life, and extend survival in patients with pancreatic ductal adenocarcinoma.

Pregabalin and its potential for abuse

The aim of this paper is to assess the substance pregabalines potential for abuse. Little information is available on the subject and that retrieved is in part conflicting. Pregabaline is likely to be abused for its positive psychological effects, e.g. euphoria. However, these effects are weak and not sustained during long-term use. Pregabaline is therefore likely to have a lower potential for abuse than benzodiazepines. In clinical studies, symptoms suggestive of physical dependence (e.g. insomnia, nausea, headache, diarrhoea) have been observed in some patients after abrupt discontinuation of pregabaline. However, available documentation indicates that pregabaline is associated with less physical and psychological dependence than benzodiazepines.

How are antibacterials used in nursing homes? Results from a point-prevalence prescription study in 44 Norwegian nursing homes†

To describe the use of antibacterials among nursing home residents in Norway according to diagnosis, therapy choice, doses and expected duration of treatment.

Advice on drug safety in pregnancy: are there differences between commonly used sources of information?

AbstractBackground and Objective: Safety regarding use in pregnancy is not established for many drugs. Inconsistencies between sources providing drug information can give rise to confusion with possible therapeutic consequences. Therefore, it is important to measure clinically important differences between drug information sources. The objective of this study was to compare two easily accessible Norwegian sources providing advice on drug safety in pregnancy — the product monographs in the Felleskatalog (FK), published by the pharmaceutical companies, and the five regional Drug Information Centres (DICs) in Norway — in addition to assessing the frequency of questions regarding drug safety in pregnancy made to the DICs according to the Anatomical Therapeutic Chemical (ATC) classification system. Methods: Advice on drug use in pregnancy provided by the DICs in 2003 and 2005 were compared with advice in the product monographs for the respective drugs in the FK. Comparison of advice was based on categorization to one of four categories: can be used, benefit-risk assessment, should not be used, or no available information. Results: A total of 443 drug advice were categorized. Seven out of ten of drugs frequently enquired about, according to the ATC system, were drugs acting on the nervous system (group N). For 208 (47%) of the drugs, advice differed between the DICs and FK. Advice from the FK was significantly (p < 0.01) more restrictive than advice from the DICs. There were no differences in the level of consistency of advice between drugs that were newly introduced and those that had been on the market for a longer time, advice regarding use of drugs in the first trimester and advice regarding use of drugs in the second or third trimester, or between advice provided during 2003 and during 2005. Conclusions: The results of this study show considerable differences between two Norwegian sources providing advice on the use of drugs in pregnancy. Based on the knowledge that healthcare providers choose sources of information in a random manner, our results may be of clinical importance. We believe that the problem with heterogeneous drug information on this subject is not confined to Norway and that our results should be of international interest.

Quality and impact of problem-oriented drug information: a method to change clinical practice among physicians?

Abstract.Objectives: Problem-oriented drug information is characterised by health professionals actively seeking drug information through various sources. In this study our objective was to determine the quality and impact of problem-oriented drug information among physicians. Methods: Evaluation forms accompanying 163 written answers to physicians from a drug information centre were used to examine the quality and impact of problem-oriented drug information during the period December 1996 to June 1998. Physicians were asked whether the preliminary telephone answer was useful and, furthermore, whether the written answer was fast enough, relevant, adequately comprehensive and had valuable references. Physicians were also asked whether the answer had caused any change in their clinical practice. If yes, they were then asked to describe the actual changes. Results: Of 163 evaluation forms, 117 (72%) were returned by physicians. Eighty-six physicians received a preliminary telephone answer and 83 (97%) stated that this was useful. Among the physicians, 92 (79%) found that the answer was fast enough, relevant, adequately comprehensive and with valuable references, while 19 (16%) found that the answer satisfied three of these four quality criteria. Seventy-one evaluation forms stated that the answer had caused a change in clinical practice. Sixty-eight (96%) of these contained a description of the change. Thirty-five evaluation forms that stated that the answers did not cause any change in clinical practice showed the same quality score as for the total group. Thus, 28 (80%) of these satisfied four and 5 (14%) satisfied three of the quality criteria. Improved routines for and control of ongoing pharmacotherapy was the most common change in clinical practice reported by physicians. Conclusion: The results show that, in general, physicians found problem-oriented drug information to be of high quality, and that it had an impact on their clinical practice. Problem-oriented drug information could be a method to change clinical practice among physicians.

Effects of MnDPDP, DPDP--, and MnCl2 on cardiac energy metabolism and manganese accumulation. An experimental study in the isolated perfused rat heart.

RATIONALE AND OBJECTIVES Recent studies indicate that manganese dipyridoxyl diphosphate (MnDPDP) may function as a slow release agent for manganese ions (Mn++) and that MnDPDP is approximately 10 times less potent than manganese chloride (MnCl2) in depressing cardiac function. The authors examined the possibility that MnDPDP and MnCl2 may influence cardiac metabolism and enzyme release and lead to a tissue accumulation of Mn. METHODS Manganese DPDP, DPDP--, or MnCl2 (1000 microM) was infused in isolated rat hearts, which were freeze-clamped at various time intervals during infusion (5 minutes) and recovery (14-minute washout). Enzyme (lactate dehydrogenase) release, tissue high energy phosphates, Mn contents, and physiologic indices were measured at various time intervals. RESULTS No significant differences were noted for: lactate dehydrogenase in the treated groups; tissue creatine phosphate (CrP) and adenosine triphosphate in MnDPDP, DPDP--, and control groups; and tissue Mn in DPDP-- and control groups. Manganese-chloride and MnDPDP-treated hearts accumulated and retained Mn in an 8:1 ratio. Manganese chloride depressed cardiac function more effectively than MnDPDP. CONCLUSIONS The study has shown that: heart tissue uptake and retention of Mn++ is rapid and effective; MnCl2 is approximately eight times more potent than MnDPDP in promoting these effects; and a rise in tissue Mn content to eight to nine times (MnDPDP) or 60 to 70 times (MnCl2) the normal level does not lead to acute side effects on cardiac energy metabolism, function, and enzyme release. The study indicates that MnDPDP may act like a slow release compound for Mn++ ions.

Assessing the effects of an intervention by a pharmacist on prescribing and administration of hypnotics in nursing homes.

Introduction: We have previously reported sub optimal use of hypnotics in geriatric institutions. In the present study we examined the intervention by a pharmacist on the prescribing and administration of hypnotics in nursing homes. Thus a follow up study was performed in 5 nursing homes included in the previous study.Method: In the period between the two surveys the pharmacist provided drug information on the rational use of hypnotics, both written and verbal, to the staff of the institutions. Data on the administration of hypnotics was obtained from the Cardex system in the institutions. Data were compared to a control group in other nursing homes, where no intervention was carried out.Results: Although the population was older in 2000 than in 1995, the proportion of patients using hypnotics (24%) was similar. Use of benzodiazepines was reduced from 81% to 40%, use of long acting benzodiazepines was reduced from 62% to 22%, and use of short‐acting hypnotics (zopiclone, zolpidem) increased from 9% to 53%. Furthermore, hypnotics administered before 9 p.m. were reduced from 40% to 14%, and the time of administration showed less variation than before. In the control population we also observed the use of short acting hypnotics in favour of benzodiazepines, similar to the results in the 5 institutions. However, in this population a significantly higher proportion of patients used hypnotics, used more than 1 hypnotic and the hypnotics were administered earlier in the evening.Conclusion: The results demonstrate an important effect of written and verbal drug information provided by a pharmacist to improve the prescribing and administration on the use of hypnotics in nursing homes.

Drug use in pregnancy—physicians' evaluation of quality and clinical impact of drug information centres

PurposeTo assess physicians’ evaluation of quality, clinical impact and ranking of Norwegian drug information centres (DICs) with regard to drug use during pregnancy.MethodsQuestionnaires were submitted consecutively to all physicians who consulted a Norwegian DIC in 2006 for information on patient-specific drug use during pregnancy.ResultsOf the 162 questionnaires sent out, 123 (76%) were returned and 117 were included in the analysis. All of the responding physicians reported that the DICs provided high-quality service in terms of providing information on drug use during pregnancy, and 92% stated that the answer from the DICs had a clinical impact. The DICs were ranked highest among the different sources providing information, and general practitioners (GP) ranked the information provided by DICs significantly higher than hospital physicians (HP).ConclusionsPhysicians consider the information provided by Norwegian DICs on drug use during pregnancy to be of high quality and of significant clinical impact. The DICs were ranked highest as a source of information among GP, suggesting that the need for prescribing support is influenced by the workplace.

A question–answer pair (QAP) database integrated with websites to answer complex questions submitted to the Regional Medicines Information and Pharmacovigilance Centres in Norway (RELIS): a descriptive study

Objective To assess a question–answer pair (QAP) database integrated with websites developed for drug information centres to answer complex questions effectively. Design Descriptive study with comparison of two subsequent 6-year periods (1995–2000 and 2001–2006). Setting The Regional Medicines Information and Pharmacovigilance Centres in Norway (RELIS). Participants A randomised sample of QAPs from the RELIS database. Primary outcome measure Answer time in days compared with Mann–Whitney U test. Secondary outcome measure Number of drugs involved (one, two, three or more), complexity (judgemental and/or patient-related or not) and literature search (none, simple or advanced) compared with χ2 tests. Results 842 QAPs (312 from 1995 to 2000 and 530 from 2001 to 2006) were compared. The fraction of judgemental and patient-related questions increased (66%–75% and 54%–72%, respectively, p<0.01). Number of drugs and literature search (>50% advanced) was similar in the two periods, but the fraction of answers referring to the RELIS database increased (13%–31%, p<0.01). Median answer time was reduced from 2 days to 1 (p<0.01), although the fraction of complex questions increased from the first to the second period. Furthermore, the mean number of questions per employee per year increased from 66 to 89 from the first to the second period. Conclusions The authors conclude that RELIS has a potential to efficiently answer complex questions. The model is of relevance for organisation of drug information centres.