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The use of anticholinergicantiparkinson agents in Norway Epidemiology, toxicology and clinical implications Thesis for the degree of Doctor Philosophiae Trondheim, November 2010 Norwegian University of Science and Technology Faculty of Medicine Department of Laboratory Medicine, Children's and Women's Health NTNU
Norwegian University of Science and Technology
Thesis for the degree of Doctor Philosophiae Faculty of MedicineDepartment of Laboratory Medicine, Children's and Women's Health ISBN 978-82-471-2407-9 (printed ver.)ISBN 978-82-471-2408-6 (electronic ver.)ISSN 1503-8181 Doctoral theses at NTNU, 2010:212 Printed by NTNU-trykk Bruk av antikolinerge antiparkinsonmedikamenter i Norge.
Epidemiologi, toksikologi og kliniske konsekvenser.
På slutten av 1990-tallet oppdaget vi at legemidlet orfenadrin, markedsført i Norge under navnet Disipal, foruroligende ofte forårsaket forgiftningsdødsfall. Orfenadrin tilhører en gammel og lite påaktet gruppe medikamenter, antikolinerge antiparkinsonmedikamenter, som opprinnelig ble brukt i behandling av Parkinsons sykdom. I to artikler i Tidsskrift for den norske legeforening advarte vi mot bruken av dette medikamentet. Etter advarselen gikk salget ned i Norge. Det var ingen tilsvarende reduksjon i Sverige og Danmark, noe som kan tyde på at advarselen i fagtidsskriftet hadde effekt på legers forskrivningspraksis. Orfenadrin ble trukket fra det skandinaviske markedet i 2005, men er fortsatt tilgjengelig i store deler av verden. Ved hjelp av data fra Reseptregisteret har vi i ettertid vist at antikolinerge antiparkinsonmedikamenter nå i all hovedsak brukes sammen med antipsykotiske legemidler, og at bruken av antikolinerge midler kan indikere forekomst av en spesiell type alvorlige bivirkninger forårsaket av slike antipsykotiske medisiner. Vi brukte denne sammenhengen for å undersøke hvilke spesifikke antipsykotiske medisiner som var tryggest å bruke. Denne tilnærmingsmåten for å vurdere legemiddelsikkerhet er på mange måter ny. Det er blitt påstått at nyere antipsykotika gir færre bivirkninger enn eldre. Vi fant stor variasjon mellom de ulike antipsykotika, men ingen systematiske forskjeller mellom eldre og yngre midler mht. sambruk med antikolinerge antiparkinsonmidler. Påstanden om at nyere antipsykotika har en generelt bedret bivirkningsprofil synes primært å dreie seg om markedsføring. Vi ønsket også å vurdere risiko for bivirkninger ved å se på hvilke medikamenter som ble foretrukket over tid. Vi antok at langtidsbruk av medisiner betyr at pasientene er fornøyde, enten fordi de opplever god virkning eller lite bivirkninger eller begge deler. Klozapin (Leponex) og zuclopentixol (Cisordinol) var de antipsykotiske medisinene som var hyppigst i kontinuerlig bruk over tre år. Vi fant en høy grad av sambruk av zuclopentixol og antikolinerge medikamenter. En forklaring kan være at effekten av zuclopentixol ble oppfattet som så god at det veide opp for bivirkningene. En slik måte å vurdere medikamenteffekt på har heller ikke vært gjort tidligere. Et overraskende og bekymringsfullt bifunn var at bruk av haloperidol (Haldol) var assosiert med betydelig overdødelighet. Dr. philos., NTNU, Det medisinske fakultet, Institutt for laboratoriemedisin, barne- og kvinnesykdommer, 251110. Veiledere: Lars Slørdal og Jørgen G. Bramness. Table of contents
1. Overview
1.2. List of papers 7 1.3. Acknowledgements 9 2. General introduction
2.1. Anticholinergic agents 10 2.2. Parkinson's disease 11 2.3. Parkinsonism 11 2.4. Efficacy and effectiveness 13 3. Introduction to the present study
3.1. Epidemiology 14 3.1.1. Clinical implications 14 3.2. Toxicology 15 3.2.1. Clinical implications 16 4. Research questions 17
5. Materials and methods
5.4 Statistics 20 6. Results
7. Discussion
7.1. Methodology 32 7.2. Main results 33 8. Conclusions 35
9. References 37
10. Appendices 41
1. Overview
This thesis is based on two fundamental questions: Which patients are currently using anticholinergic antiparkinson drugs? Does it matter which anticholinergic antiparkinson drug they are using? These questions were further investigated, using a variety of methods, as follows: Are anticholinergic antiparkinson agents predominantly used to treat Parkinson's disease or antipsychotic induced extrapyramidal side-effects Is there a high risk of abuse of anticholinergic antiparkinson agents? Can alleged differences in receptor binding profiles of typical first- (FGA) and atypical second (SGA) -generation antipsychotic agents predict concomitant use of anticholinergic agents? Can long-term co-prescription of anticholinergic antiparkinson agents shed some light on the efficacy of antipsychotic agents? Does the literature indicate differences in toxicity and fatality rates of anticholinergic antiparkinson agents? Does an autopsy material indicate differences between anticholinergic agents regarding toxicity and fatality Are warnings in a medical journal against the use of the most toxic anticholinergic agent enough to reduce its use? Can patients stop using anticholinergic agents without further remedies? The thesis has the following conclusions: The overwhelming majority of anticholinergic users were patients concomitantly using antipsychotic agents, presumably for the alleviation of antipsychotic induced EPS. The use of anticholinergics was not particularly skewed and we could not find any other indication of abuse, indicating that concomitant use of anticholinergics can be a proxy for the liability of specific antipsychotic agents to cause EPS. For patients using only one antipsychotic agent, the concurrent use of anticholinergics varied between 0.4% and 26.0%, but largely independently of the distinction between typical and atypical antipsychotics. High D2-receptor antagonism and a high 5-HT2A/D2- receptor-affinity ratio coincided with the use of anticholinergics. Clozapine and zuclopentixol demonstrated the highest level of prescription persistence in a three-year period. The high prevalence of concomitant use of anticholinergics and zuclopentixol may indicate that the latter was considered efficacious enough to outweigh its probable side-effects. Haloperidol was associated with a mortality three times that of any other antipsychotic agent in the study. Orphenadrine is by far the most toxic anticholinergic antiparkinson agent with a high mortality risk. Warnings in a medical journal against the use of a toxic drug can have an impact on prescription patterns. At least one-third of the patients using anticholinergic antiparkinson agents do not need them. 1.2 List of papers Gjerden P, Bramness JG, Slørdal L: The use and potential abuse of anticholinergic antiparkinson drugs in Norway. A pharmacoepidemiological study. British Journal of Clinical Pharmacology, 2008; 67(2), 228-233. Gjerden P, Slørdal L, Bramness JG: Association between the use of anticholinergic antiparkinson drugs and safety and receptor drug-binding profiles of antipsychotic agents. European Journal of Clinical Pharmacology, 2009; 65(12): 1229-1235. Gjerden P, Slørdal L, Bramness JG: Prescription persistence and safety of antipsychotic medication: a national registry-based three-year follow-up. European Journal of Clinical Pharmacology, 2010; 66: 911-917. Gjerden P, Slørdal L: Antikolinerge antiparkinsonmedikamenters kliniske farmakologi. En oversikt med vekt på akutt toksisitet. Tidsskrift for Den norske lægeforening, 1998; 118: 53-55. Gjerden P, Engelstad KS, Pettersen G, Slørdal L: Dødsfall forårsaket av antikolinerge antiparkinsonmedikamenter. Analysefunn i et nasjonalt 11-årsmateriale. Tidsskrift for Den norske lægeforening, 1998; 118: 42-44. Gjerden P, Bramness JG, Slørdal L: Effect of warnings in a medical journal on the use of orphenadrine. Journal of Evaluation in Clinical Practice, 2008; 14: 615-617. Gjerden P, Slørdal L, Bramness JG: The use of antipsychotic and anticholinergic antiparkinson drugs in Norway after the withdrawal of orphenadrine. British Journal of Clinical Pharmacology, 2009; 68(2): 238-242. 1.3 Acknowledgements This thesis is the conclusion of a task that started an evening 13 years ago when Lars Slørdal and I was discussing anticholinergic antiparkinson agents while nurturing a beer at Oslo Mikrobryggeri. Before this evening I was under the assumption that all anticholinergic antiparkinson agents were equal and of no particular concern, neither to psychiatrists nor their patients. Lars, at that time working at the National Institute of Forensic Toxicology in Oslo, had made a note of some drug-related deaths involving orphenadrine. This triggered our interest in this group of drugs, eventually resulting in this thesis. Without the scientific curiosity and ongoing interest displayed by Lars, this work would never have been done. Thank you, Lars, you are my brother! Jørgen G. Bramness had read our first articles and found the topic interesting. He was at that time working with the Norwegian Prescription Database at the Norwegian Institute of Public Health in Oslo and saw some interesting possibilities in the use of this database. Thank you, Jørgen, for your enthusiasm, creativity and effectiveness! I would like to thank Telemark Hospital, Department of Psychiatry, for granting me the time and the facilities I needed to write this thesis. The librarian at Telemark Hospital, Mirjam Håndlykken, has been very helpful. I would also like to thank the staff at ward 1A, in particular Inger T. Asheim, who has been very patient and managed without me for extended periods of time. Finally I thank my wife, Torbjørg Straand, for support and encouragement. Without her, this work would not be 2 General introduction
2.1 Anticholinergic agents Acetylcholine acts at two different classes of cholinergic receptors, nicotinic ligand-gated ion channels and G-protein-coupled muscarinic receptors. Both confer a wide range of effects in the periphery as well as the central nervous system (1). Acetylcholinesterase inhibitors, used in the treatment of Alzheimer's disease, are the best known modulators of nicotinic receptor function. The class of drugs called anticholinergic agents acts as competitive antagonists at muscarinic receptors only and should more precisely be named antimuscarinic agents. However, the term anticholinergic agents is the term used in the official nomenclature of World Health Organization (WHO) and is thus adopted throughout this thesis (2). Anticholinergic agents have been known in many cultures for thousands of years. The prototype of the muscarinic antagonists, atropine, is naturally occurring in Atropa belladonna and several other members of the Solanaceae genus of plants (1). These naturally occurring anticholinergic agents have been used for a variety of reasons through history. The term belladonna refers to the beautiful women of Italy who considered the mydriatic effect aesthetically desirable. The first man-made anticholinergic agents were introduced in 1946, trihexyphenidyl/benzhexol and biperiden followed by procyclidine, benztropine and, lastly, orphenadrine in 1951 (3-10). The effect conferred by these agents on Parkinson's disease and neuroleptic-induced parkinsonism is assumed to be mediated by reducing the imbalance between cholinergic and dopaminergic activity in nigrostriatal neurons. Orphenadrine confers a wide range of effects in addition to muscarinic 2.2 Parkinson's disease James Parkinson published "An essay on the shaking palsy" in 1817. Although incomplete, this was the first description of a clinical condition that Jean-Martin Charcot half a century later named "maladie de Parkinson". The medically correct term paralysis agitans has never been as popular in clinical use as Parkinson's disease. First thought to be a nosological entity, its heterogeneity makes it more correct to use the term Parkinson's syndrome instead of Parkinson's disease. The classic symptoms tremor, rigidity and bradykinesia are assumed to find their primary neurological substrate in the loss of dopaminergic neurons in the nigrostriatal pathway, although the pathogenetic process behind this deficiency may vary (12-14). The first medicinal intervention was the administration of extract from Atropa belladonna in 1867. From the late 1940s onwards synthesized anticholinergic agents came into extensive use. Until the development of L-dopa in the early 1960s, they were the mainstay of Parkinson's disease treatment (12). The medical treatment of Parkinsons' disease has made further progress since then (15). 2.3. Parkinsonism Before antipsychotic agents came into use the terms Parkinson's disease and parkinsonism were used synonymously. Following the introduction of chlorpromazine in 1952, the propensity of antipsychotic agents to induce parkinsonian symptoms was recognized and eventually named parkinsonism (drug-induced parkinsonism), as a entity different from, but mimicking, Parkinson's disease (idiopathic parkinsonism). At first it was regarded as a clinical manifestation of the desirable pharmacological action and it took many years before it was considered an undesirable adverse effect. Sedation, anticholinergic effects and hypotension were the acknowledged side-effects of the early low-potency agents and it was not until the introduction of the more potent and specific D2 receptor antagonists, culminating with the synthesis of haloperidol in 1958, that parkinsonian adverse effects were recognized as a major problem. Eventually, drug-induced parkinsonism came to be considered the most serious hindrance for the use of antipsychotic agents and a diminished liability to promote parkinsonism became the main argument in the endeavour to define a new generation of antipsychotics (16). The first - some would say the only - atypical antipsychotic agent was clozapine, demonstrating virtually no parkinsonian side-effects. Clozapine was marketed from the early 1970s, withdrawn because of its significant haematological toxicity and reintroduced in the 1990s because of its unique efficacy. In a quest to replicate the efficacy and lack of abnormal motor symptoms demonstrated by clozapine, avoiding its haematological side-effects, a number of novel atypical antipsychotic agents have been synthesized in the last decade (17). Abnormal motor symptoms caused by antipsychotic agents are usually named extrapyramidal side-effects (EPS) and most often sub-divided into acute dystonia, parkinsonism and akathisia, thus defining tardive dyskinesia as an entity of its own. Some authors, however, include tardive dyskinesia as an EPS. In clinical practice, the terms EPS and parkinsonism are often used as synonyms, while akathisia and tardive dyskinesa are described as separate entities. Acute dystonia, being an acute condition, is mostly confined to hospitalized patients and should have little bearing on any of the papers that constitute this thesis. 2.4 Efficacy and effectiveness
The terms efficacy and effectiveness are frequently used in the medical literature. Seemingly similar in meaning, they express different concepts. The term efficacy refers to the question if a treatment works under ideal condition, the randomized controlled trial (RCT) being the archetypal example. The term effectiveness refers to the question if the treatment works in everyday life. If the treatment does more harm than good to the patient, possibly because of bothersome side-effects, the treatment might be rejected and is thus ineffective although it may be efficacious (18). There has been a growing difficulty in translating the results of RCTs into clinical practice concerning the clinical usefulness of old and newer antipsychotic agents (19). 3 Introduction to the present study
3.1. Epidemiology The use of anticholinergic agents in Parkinson's disease has been in decline, at least in the industrialized countries of the world, but its use is not altogether obsolete (20). The low cost incurred by its use is probably the reason for the not insignificant use of these drugs against Parkinson's disease worldwide. In Norway, the use of anticholinergic agents was assumed to be largely confined to treating antipsychotic induced side- effects. This assumption had, however, not been formally investigated. Paper 1 delineates the prevalence and indication of use of anticholinergic antiparkinson drugs in Norway and investigates possible abuse of these drugs. The users of anticholinergic antiparkinson drugs are further scrutinized in Paper 2, assessing the concomitant use of anticholinergic and antipsychotic agents. 3.1.1. Clinical implications The prevalence of antipsychotic induced EPS has been much debated. Second-generation antipsychotic agents (SGAs) have been claimed to confer a much lower risk of inducing EPS than first-generation antipsychotics (FGAs). This notion has been challenged in the last few years, in the wake of two large clinical studies that failed to demonstrate any difference between FGAs and SGAs in this respect (21, 22). A confounding factor is that almost all studies of drug-induced EPS have been carried out with schizophrenic patients, a group of patients with an inherent tendency of developing both parkinsonism and tardive dyskinesias even in the absence of antipsychotic agents. We found that the overwhelming majority of anticholinergic antiparkinson drugs were used concomitantly with antipsychotic agents, presumably for the amelioration of antipsychotic induced EPS. We could not find indications of a skewed use of anticholinergic drugs. Consequently we assumed that concomitant use of anticholinergics might reflect perceived EPS and that concomitant use of anticholinergics could be used as a proxy for antipsychotic induced EPS. In particular we investigated potential differences between FGAs and SGAs. Paper 2 focuses on differences in the liability of antipsychotic agents to cause EPS and explores some pharmacodynamic differences between FGAs If doctors and patients stick to a single antipsychotic agent for years, one might assume that both efficacy and lack of side-effects is considered satisfactory and that the drug has demonstrated effectiveness. In addition to assessing prescription persistence as a proxy for the real-life effectiveness of antipsychotic agents, Paper 3 compares concomitant prescription of anticholinergic antiparkinson agents and mortality as indicators of safety of antipsychotic agents. In addition, long-term concomitant prescription of antipsychotic and anticholinergic agents is used in an indirect evaluation of the efficacy of some of the antipsychotic agents in the study. Anticholinergic antiparkinson agents constitute a very old class of drugs. They were introduced at a time when preclinical trials were less comprehensive than today and pharmacokinetics and metabolism were scantily described before marketing. This is still the case. Scattered case- reports have been published but, to our knowledge, no review that deals comprehensively with the toxicology of anticholinergic antiparkinson drugs. Standard psychiatric textbooks do not differentiate between the various anticholinergics. Paper 4 is a review of the clinical pharmacology of the three anticholinergic antiparkinson drugs marketed in Norway at the time of the study, with emphasis on acute toxicity. Paper 5 is a study of a series of fatalities caused by anticholinergic antiparkinson drugs in Norway in an 11-year period. 3.2.1. Clinical implications The toxicology of anticholinergic antiparkinson agents is not the same. The results from Papers 4 and 5 indicate that orphenadrine stands out from the rest, being responsible for a disproportionately large number of overdose deaths. Consequently, in Paper 5 we warned against the use of orphenadrine. Journal reading is probably the most popular form of continuous medical education but it is difficult to demonstrate an effect on doctors' professional behaviour (23, 24). Studies reporting positive effect of passive educational initiatives are very scarce (25). Paper 6 examines whether warnings in a medical journal against the use of orphenadrine had any effect on the sales of this compound in Norway. Eventually, orphenadrine was withdrawn from the Scandinavian market. Paper 7 focuses on the consequences for the patients when they stopped using orphenadrine, regarding the use of anticholinergic and antipsychotic agents. 4 Research questions
This work elaborates on two basic questions: Which patients are presently using anticholinergic antiparkinson drugs? Does it matter which anticholinergic antiparkinson drug they are using? The respective answers to these questions consequently led to the following research questions that this thesis aims to answer: 1. It is assumed that the use of anticholinergic antiparkinson agents today is mainly confined to the alleviation of antipsychotic induced EPS. Is this assumption correct? This question is dealt with in Paper 1. 2. The reported risk of abuse of anticholinergic antiparkinson agents varies considerably in the literature. Is there a high risk of abuse of these drugs? This question is also dealt with in Paper 1. 3. The reported prevalence of antipsychotic induced EPS differs significantly in the literature. In particular, newer studies have questioned the alleged diminished liability of the atypical second- generation antipsychotics to induce EPS. Is the prevalence of drug-induced EPS the same for all antipsychotic agents? Is there a difference between FGAs and SGAs in this aspect? Can alleged differences in receptor binding profiles of FGAs and SGAs predict concomitant use of anticholinergic agents? Paper 2 deals with these questions. 4. Paper 3 deals with prescription persistence and safety, including mortality, associated with antipsychotic medication. Are there any differences between the various antipsychotics? Can concomitant use of anticholinergic agents help differentiate efficacy from perceived side-effects as possible reasons for long-term prescription persistence of antipsychotic agents? 5. What does the literature tell us about the toxicity and fatality risk of anticholinergic antiparkinson drugs? Do these drugs differ from each other in this aspect? Paper 4 deals with this question. 6. Are there differences in toxicity between anticholinergic antiparkinson agents in a Norwegian autopsy material? This question is dealt with in Paper 5. 7. Papers 4 and 5 delineate orphenadrine as a drug quite different from the rest of the anticholinergic antiparkinson agents, carrying a significantly higher risk of death than any other anticholinergic agent. Will a warning against the use of orphenadrine result in a decline of the use of this drug? Paper 6 deals with this question. 8. Can patients stop using orphenadrine or other anticholinergic antiparkinson drugs when they have to, without reducing antipsychotic dosage, switching antipsychotic agent or replacing one anticholinergic agent with another? Paper 7 deals with these 5 Material and methods
Papers 1, 2, 3 and 7 are pharmacoepidemiological studies. Paper 4 is a literature review while Paper 5 is a retrospective study of a series of autopsy cases. Paper 6 is a naturalistic study with case-control elements. Papers 1, 2, 3 and 7 are based on the Norwegian Prescription Database (NorPD) which covers sales of drugs to the entire Norwegian outpatient population from 2004. Paper 4 is based on an extensive literature search in various databases. The basis for Paper 5 is autopsy samples received at the National Institute of Forensic Toxicology during the years 1986 – 1996. Paper 6 compares drug sales to the entire Norwegian, Swedish and Danish outpatient population as reported to the national health Papers 1, 2, 3 and 7 uses one-year prevalence as the basic measure and collects standard pharmacoepidemiological data from NorPD for this period of time. In addition to standard epidemiological calculations, we also found Lorenz curves and Gini coefficients useful in the evaluation of possible drug abuse in Paper 1. Paper 2 extracts antipsychotic receptor profiles from a previously published external source. Paper 6 uses standard epidemiological data and calculations. The main statistical methods used in the present analyses are simple frequency analyses performed in SPSS 15.0 using Pearson's chi-square (²) test for the assessment of significance. In addition, Spearman's rank correlation coefficient () was used in Paper 2 and binary logistic regression analyses with odds ratios were performed in Paper 3. 6 Results
The use and potential abuse of anticholinergic antiparkinson drugs
in Norway. A pharmacoepidemiological study.
Pål Gjerden, Jørgen G. Bramness, Lars Slørdal British Journal of Clinical Pharmacology 2008; 67(2): 228-233 The use of anticholinergic antiparkinson drugs is assumed to have shifted from the therapy of Parkinson's disease to the amelioration of extrapyramidal adverse effects induced by antipsychotic drugs. There is a considerably body of data suggesting that anticholinergic antiparkinson drugs have a potential for abuse. The aim was to investigate the use and potential abuse of this class of drugs in Norway. Data were drawn from the Norwegian Prescription Database on sales to a total of 73 964 patients in 2004 of biperiden and orphenadrine, and use in patients with Parkinson's disease or in patients who were also prescribed antipsychotic agents. Possible abuse of these drugs was assessed by the level of use, skewedness of use, indications of drug-seeking behaviour and concomitant use of benzodiazepine tranquillizers, a group of drugs with a recognized potential for abuse. Patients using antipsychotic medication accounted for 94% of the use of anticholinergics, compared with 4.3% with Parkinsons'disease. We found indications of abuse of benzodiazepine tranquillizers among patients using antipsychotics, but there were no clear indications of abuse of anticholinergics, even among patients who were strongly suspected of abuse of bezodiazepines. Anticholinergic antiparkinson drugs were primarily used by patients with psychotic illnesses. These patients have a very high prevalence of legal and illegal drug abuse, but the risk of abuse of anticholinergic antiparkinson drugs seemed small. Association between the use of anticholinergic antiparkinson drugs
and safety and receptor drug-binding profiles of antipsychotic agents
Pål Gjerden, Lars Slørdal, Jørgen G. Bramness European Journal of Clinical Pharmacology 2009; 65(12): 1229-1235 The use of anticholinergic antiparkinson drugs is almost exclusively confined to treating antipsychotic-induced extrapyramidal side-effects (EPS). We investigated the prevalence of concomitant prescription of anticholinergics as a proxy for antipsychotic-induced EPS and compared variance in prevalence with differences in the assumed mechanisms of action of antipsychotics on central nervous system (CNS) transmitter systems (i.e., receptor drug-binding profiles). We paid special attention to potential differences between typical and atypical antipsychotics. Data were drawn from the Norwegian Prescription Database on sales of antipsychotic and anticholinergic antiparkinson drugs to a total of 57 130 outpatients in 2004. We assessed concomitant dispensations of antipsychotic and anticholinergic drugs and correlated the prevalence of concomitantly prescribed anticholinergics to previously assessed receptor-binding profiles of antipsychotics. The concurrent use of anticholinergics varied between 0.4% and 26.0% for patients using a single antipsychotic agent. The prevalence of anticholinergic comedication was more than twice as high in patients using two or more antipsychotic drugs. Four typical antipsychotics (fluphenazine, zuclopentixol, haloperidol and perphenazine) were associated with higher concomitant use of anticholinergics than the rest. For the remaining 14 antipsychotic agents, the difference between typical and atypical antipsychotics was neither pronounced nor systematic. A high degree of D2-receptor antagonism and a high 5-HT2A/D2-receptor- affinity ratio coincided with the use of anticholinergics. The liability of antipsychotic drugs to cause EPS seemed to vary considerably and largely independently of the distinction between typical and atypical antipsychotics. Prescription persistence and safety of antipsychotic medication: a
national registry-based three-year follow-up
Pål Gjerden, Lars Slørdal, Jørgen G. Bramness European Journal of Clinical Pharmacology 2010; 66: 911-917 Long-term persistence of use, lack of co-prescribed anticholinergic antiparkinson drugs and low mortality may indicate effectiveness and safety of antipsychotic drugs. We aimed to assess three-year prescription persistence, concomitant use of anticholinergic antiparkinson agents and mortality related to the use of all antipsychotic agents available in Data were drawn from the Norwegian Prescription Database on the sales of antipsychotic and anticholinergic antiparkinson agents in 2004 to a total of 52 427 patients. The primary study group was a subgroup of 34 494 patients who were prescribed only one antipsychotic agent in 2004. The patients were re-investigated in 2007. For each of the 13 antipsychotic agents studied, assumed prescription persistence was assessed in light of use of anticholinergic antiparkinson agents in 2004 and casualty rates were noted. The highest persistence was demonstrated by zuclopenthixol (69.8%) and clozapine (88.4%). Zuclopenthixol was often co-prescribed with anticholinergics (22.2%), in contrast to clozapine (3.6%). Ziprasidone was associated with a low mortality (OR=0.08), while chlorprotixene and haloperidol were associated with a high mortality (OR=1.34 and 3.97, respectively) compared to levomepromazine. Clozapine demonstrated a high degree of continuity of prescription and a low level of concomitant use of anticholinergics. Zuclopenthixol also demonstrated a high degree of continuity of prescription, despite a considerable degree of co-prescribed anticholinergics. We did not find that any other antipsychotic than ziprasidone was associated with a low mortality. The use of haloperidol seemed to confer a mortality risk three times that of any of the other antipsychotic agents included. The clinical pharmacology of anticholinergic antiparkinson drugs: a
review with emphasis on acute toxicity
Pål Gjerden, Lars Slørdal Tidsskrift for Den norske lægeforening 1998; 118: 53-55 Anticholinergic antiparkinson drugs are primarily used to ameliorate extrapyramidal side-effects induced by neuroleptic agents. In 1998 orphenadrine dominated quantitatively among these drugs in Norway, presumably because it was assumed to carry a lower risk of abuse. There are numerous reports of deaths following orphenadrine overdoses. Orphenadrine has complex pharmacokinetic properties and a narrow therapeutic index. After an overdose, it confers toxic effects of rapid onset to several organ systems. No specific and effective therapy for orphenadrine intoxications has been established. For the two other drugs in this class which were marketed in Norway at this time, biperiden and benztropine, toxicity is mainly connected to their anticholinergic properties. Notably, no reports of lethalities after overdoses of biperiden seem to be available. A small number of accounts of deaths following benztropine intoxications have been published. Neither of these two agents, and benztropine in particular, has been subjected to comprehensive pharmacokinetic evaluations. The relatively extensive use of orphenadrine should be discouraged. Fatalities caused by anticholinergic antiparkinson drugs: a
retrospective study of a series of Norwegian cases
Pål Gjerden, Karen Sofie Engelstad, Grete Pettersen, Lars Slørdal Tidsskrift for Den norske lægeforening 1998; 118: 42-44 All autopsy samples received at the National Institute of Forensic Toxicology during the years 1986-1996 which contained anticholinergic antiparkinson drugs were reviewed. Of a total of 69 cases, orphenadrine was present in 57 (83%), biperiden in 8 (12%), procyclidine in 3 (4%) and trihexyphenidyl/benzhexol in 1 (1%) of the subjects. The measured concentrations were assessed in light of previously published data. Of 21 cases where causality between drug ingestion and death was classified as either highly probable (18/21) or possible (3/21), all subjects tested positive for orphenadrine. In the autopsy samples from these patients, orphenadrine concentrations in the 4.5 – 600 mol/l range (mean 62.5 mol/l, SD 126.5 mol/l) were determined. Because of a low national autopsy rate, there is reason to believe that the actual numbers of drug- related deaths in this period may have been significantly higher. It is concluded that orphenadrine is responsible for a disproportionately high number of overdose deaths. Effect of warnings in a medical journal on the use of orphenadrine
Pål Gjerden, Jørgen G. Bramness, Lars Slørdal Journal of Evaluation in Clinical Practice 2008; 14: 615-617 The effect of journal reading on doctors' professional behaviour has not been extensively studied. We have tried to assess the impact of a warning against the use of orphenadrine published in an extensively circulated Norwegian medical journal. Based on evidence of excessive toxicity we published a warning against the use of orphenadrine in the Journal of the Norwegian Medical Association in 1998. There were no such initiatives in neighbouring Scandinavian countries. Yearly sales data for orphenadrine in Norway were compared to sales data from Sweden and Denmark before and after Sales data showed a steeper decline in the prescription of orphenadrine in Norway compared to Sweden and Denmark from the time of intervention in 1998 until the drug was withdrawn from the Scandinavian market in The results of the media alert support the assumption that professional initiatives in a medical journal may alter established prescription The use of antipsychotic and anticholinergic antiparkinson drugs in
Norway after the withdrawal of orphenadrine
Pål Gjerden, Lars Slørdal, Jørgen G. Bramness British Journal of Clinical Pharmacology 2009; 68(2): 238-242 Extrapyramidal side-effects induced by antipsychotic drugs are treated with dose reduction or substitution with another antipsychotic drug or by the addition of anticholinergic antiparkinson agents. The withdrawal of orphenadrine from the Norwegian market provided a possibility to investigate to what degree these alternative measures were taken in clinical practice. Data were drawn from the Norwegian Prescription Database on the sales of antipsychotics and one of the two anticholinergic antiparkinson agents marketed in 2004, orphenadrine and biperiden, to a total of 39 758 outpatients. These patients were reinvestigated in 2007. The consequences of the withdrawal of orphenadrine from the Norwegian market in 2005 regarding dosing, switching and cessation of antipsychotics and use of anticholinergics were assessed for orphenadrine users compared with biperiden users. Of the patients originally using orphenadrine, 28.4% stopped using the drug without reducing the antipsychotic dose or replacing orphenadrine with another anticholinergic agent. The corresponding number for biperiden users was 19.3%. Only 11.8% of patients switched to another antipsychotic drug, but they used significantly lower antipsychotic doses than those who stayed on the same drug. The use of anticholinergic antiparkinson agents could be seen as superfluous for at least one-third of the patients. 7 Discussion
This thesis employs a variety of scientific methods. Four of the papers are pharmacoepidemiological studies. Pharmacoepidemiology is the study of the use of and the effects of drugs in large numbers of people (26). It is a relatively new applied field and from the beginning has primarily concerned itself with the study of adverse drug effects, in particular drug effects that are uncommon, not dose-related and unpredictable. Preclinical toxicity testing has been mandatory for medicinal drugs since the 1938 Food, Drug, and Cosmetic Act was passed in the US. Drug surveillance programs were developed in the 1950s but it was the "Thalidomide disaster" of the early 1960s that demonstrated that epidemiological methods could make significant contributions to the study of drug effects in humans. The teratogenicity of thalidomide was only revealed a number of years after the compound had been introduced as a harmless drug for treating insomnia and morning sickness in pregnant women. Premarketing studies of drug effects are limited in size and time, usually include homogenous groups of subjects, exclude important subgroups and are most often compared to placebo instead of the best available drugs for the same indication. Postmarketing pharmacoepidemiological studies are much larger, include patients not studied prior to marketing, include patients using other drugs, can discover uncommon or delayed effects and can assess much larger numbers of drugs. The Norwegian Prescription Database contains information on all drugs filled by individual patients living outside institutions in Norway from 1 January 2004, covering the entire population of 4.6 million inhabitants. The magnitude and completeness of this database makes it rather unique. The remaining three studies employ other methods. The literature review of orphenadrine in Paper 4 seems to be the first of its kind since 1982 (27). Several highly relevant papers dealing with orphenadrine have been published in non-indexed, non-English journals, including Dutch periodicals. This may partly explain why orphenadrine has been on the market world-wide for so long, 7.2 Main results This thesis reports on the use as well as the qualities of anticholinergic agents. In some aspects it also transcends anticholinergic agents by evaluating antipsychotic agents, both as a class and as individual drugs. The thesis reports a number of strictly epidemiological findings concerning the users of anticholinergic antiparkinson agents and the selection of anticholinergic agents following warnings in a medical journal and restrictions in availability. It argues that at least one third of the use of anticholinergics is superfluous. In addition, the thesis seems to allow drawing certain conclusions regarding the innate qualities of anticholinergic agents: The risk of abuse of anticholinergics is low. Toxicity and mortality differs significantly within this class of drugs and orphenadrine stands out as a particularly toxic drug. The most original contributions made by this thesis are the results that transcend anticholinergic agents: The liability of specific antipsychotic agents to cause EPS can be compared by the concomitant use of anticholinergics. The concurrent use of anticholinergics demonstrates that the classification of antipsychotic agents as typical first-generation or atypical second- generation does not correspond with the alleged criteria for this classification. Concomitant use of anticholinergics in long-term antipsychotic medication may even be a contributory factor for the evaluation of the efficacy of specific antipsychotic agents, not only their effectiveness. The disproportionately high mortality confined to long-term prescription of haloperidol must be considered an important but chance finding, a finding supported by other studies but not 7 Conclusions
In Norway in 2004 an overwhelming majority of the anticholinergic users were patients concomitantly using antipsychotic agents. We assumed that the reason for this use was EPS induced by antipsychotic drugs and the presumed alleviation of these symptoms by anticholinergic We also found that the use of anticholinergic agents was not very skewed and we did not find any other indications of abuse of anticholinergic The lack of skewedness, together with the narrow indication for the use of these drugs, instigated the possibility of using the prevalence of concomitantly prescribed anticholinergics as a proxy for the prevalence of the respective antipsychotic agents' liability to cause EPS. The exact prevalence could not be estimated, but the relative risk of each antipsychotic drug to cause EPS compared to the corresponding risk of other antipsychotics should be fairly accurately assessed. The prevalence of drug-induced parkinsonism varied significantly, but largely independently of the classification of an antipsychotic drug as either FGA or SGA. Long-term prescription persistence of a specific antipsychotic agent can be a proxy for its effectiveness. Concomitant use of anticholinergic antiparkinson drugs can be a proxy for antipsychotic induced EPS. Comparing long-term use of both antipsychotic and anticholinergic agents may indirectly be used in the evaluation of the efficacy of antipsychotic agents. The literature clearly demonstrates a difference between the various anticholinergics regarding toxicity and mortality. When we retrospectively studied a series of fatality cases the finding was the same, namely that orphenadrine had been causing a disproportionately high number of deaths compared to the other anticholinergic agents. When we warned against the use of orphenadrine in Norway, the use declined significantly compared to Sweden and Denmark. When orphenadrine was withdrawn from the market and the patients had to stop using this drug, one third of them managed to do so without reducing antipsychotic dosage, switching antipsychotic agent or using another anticholinergic agent. At least one third of the patients using anticholinergic agents probably did not need them. A surprise finding was that every fourth patient being prescribed haloperidol was dead in three years. Haloperidol was associated with a mortality three times that of any of the other antipsychotic agents included in the study. 9. References
1. Nemeroff CB, Putnam JS. Anticholinergics and Amantadine. In: Kaplan & Sadock's Comprehensive Textbook of Psychiatry, eds Sadock JB, Sadock VA. Philadelphia: Lippincott Williams & Wilkins, 2005; 2727-2732 2. WHO Collaborating Centre for Drug Statistics Methodology. Guidelines for ATC classification and DDD assignment. WHO 3. Corbin KB. Trihexyphenidyl. Evaluation of the new agent in the treatment of Parkinsonism. JAMA 1949; 141(6): 377-382 4. Miller J. The effects of biperiden hydrochloride (Akineton) in post-encephalitic Parkinsonism. Scot Med J 1964; 9: 391-393 5. Duffin WM, Green AF. The pharmacological properties of the optical isomers of benzhexol, procyclidine, tricyclamol and related compounds. Br J Pharmacol 1955; 10: 383-386 6. Zier A, Doshay LJ. Procyclidine hydrochloride (Kemadrine) treatment of Parkinsonism. Result in 108 patients. Neurology 1957; 7: 485-489 7. Doshay LJ. Five-year study of benztropine (Cogentin) methanesulfonate. Outcome of 302 cases of paralysis agitans. JAMA 1956; 162(11): 1031-1034 8. Gillespy RO, Hall Ratcliffe A. Treatment of Parkinsonism with a new compound (B.S.5930). Br Med J 1955; Aug. 6: 352-355 9. Doshay LJ, Constable K. Treatment of paralysis agitans with orphenadrine (Disipal) hydrochloride. Results in 176 cases. JAMA 1957; 163(15): 1352-1357 10. Rosenfeld S, Nayampalli SS, Goldner MG. An evaluation of orphenadrine hydrochloride (Disipal). J Am Ger Soc 1959; 7(6): 11. Dollery C. (ed.) Therapeutic drugs. 2. ed., Edinburgh: Churchill Livingstone 1999 12. Gøtz W. Geshickte der therapie des Morbus Parkinson. Pharm Unsere Zeit 2006; 35(3): 190-196 13. Calne DB. Parkinson's disease over the last 100 years. Adv Neurol 2003; 91: 1-8 14. Burch D, Sheerin F. Parkinson's disease. Lancet 2005; 365: 622- 15. Jankovic J, Aguilar LG. Current approaches to the treatment of Parkinson's disease. Neuropsychiatr Dis Treat 2008; 4(4): 743- 16. Janiack PG, Beedle D. Medication-induced movement disorders. In: Kaplan & Sadock's Comprehensive Textbook of Psychiatry, eds Sadock JB, Sadock VA. Philadelphia: Lippincott Williams & Wilkins, 2005; 2712-2718 17. van Kammen DP, Marder SR. Serotonine-dopamine antagonists (Atypical or second-generation antipsychotics). In: Kaplan & Sadock's Comprehensive Textbook of Psychiatry, eds Sadock JB, Sadock VA. Philadelphia: Lippincott Williams & Wilkins, 2005; 18. Pittler MH, White AR. Efficacy and effectiveness. Focus Alternat Complement Ther 2005 19. Fleischhacker WW, Goodwin GM. Effectiveness as an outcome measure for treatment trials in psychiatry. World Psychiatry 2009; 20. Katzenschlager R, Sampaio C, Costa J, Lees A. Anticholinergics for symptomatic management of Parkinson's disease. Cochrane Database of Systematic Reviews 2003, Issue 2. Art. No.: CD003735. DOI: 10.1002/14651858. 21. Lieberman JA, Stroup TS, McEvoy JP, Swartz MS, Rosenheck RA, Perkins DO, Keefe RSE, Davis SM, Davis CE, Lebowitz BD, Severe J, Hsiao JK. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med 2005; 353: 22. Jones PB, Barnes TRE, Davies L, Dunn G, Lloyd H, Hayhurst KP, Murray RM, Markwick A, Lewis SW. Randomized controlled trial of the effect on quality of life of second- vs. first generation antipsychotic drugs in schizophrenia. Arch Gen Psychiatry 2006; 63: 1079-1087 23. Oxman AD, Thomson MA, Davis DA, Haynes RB. No magic bullets: a systematic review of 102 trials of interventions to improve professional practice. Can Med Assoc J 1995; 153: 24. Davis DA, Thomson MA, Oxman AD, Haynes RB. Evidence for the effectiveness of CME: a review of 50 randomized controlled trialøs. JAMA 1992; 268: 1111-1117 25. Figueiras R, Sastre I, Gestal-Otero JJ. Effectiveness of educational interventions on the improvement of drug prescription in primary care: a critical literature review. J Eval Clin Pract 2001; 7(2): 223-241 26. Strom BL. What is pharmacoepidemiology? In: Pharmacoepidemiology, ed Strom BL. Hoboken: John Wiley & Sons, 2000; 3-15 27. Sangster B. Orphenadrine intoxication. Geneesmiddelen Bull 10 Appendices
Is not included due to copyright Is not included due to copyright Is not included due to copyright Is not included due to copyright Is not included due to copyright The lower panel in Figure 1 in Paper 6 (Effect of warnings in a medical journal on the use of orphenadrine), does not differentiate Denmark from Sweden. The curve for Denmark starts slightly below the curve for Sweden and ends higher. In the published version of Paper 3 (Prescription persistence and safety of antipsychotic medication: a national registry-based 3-year follow-up) the following changes have been made compared to the original manuscript (the original version in square brackets): Table 2: "Risk of death by the end of 2007 for patients using
antipsychotic drugs in 2004, expressed as odds ratio (OR) and 95%
confidence interval (CI)…" [Odds ratio (OR) for patients using
antipsychotic drugs in 2004 of having died at the end of 2007.]
Table 3: "Likelihood that patients using antipsychotic drugs in 2004
would remain with the same antipsychotic drug in 2007, expressed as
odds ratio (OR) and 95% confidence interval (CI)…" [Odds ratio (OR)
for patients using antipsychotic drugs in 2004 of staying with the same
antipsychotic drug in 2007.]
Introduction: "…, all antipsychotic agents would be evaluated in the
same way." […, this would require that all antipsychotic agents were
evaluated in the same way.]
Material and methods: "…, use of a drug primarily in institutions might
indicate that psychiatrists prefer it as treatment for the most severely…"
[…, drugs which were primarily used in institutions might indicate which
drugs the psychiatrists preferred as treatment for the most severely…]
"comprised patients" [was constituted by patients] Results: "the group using chlorprotixene" [the chlorprotixene using
group]
"…, use of anticholinergics and use of specific antipsychotics " […, if the patient used anticholinergics and the use of specific antipsychotics] Discussion: "prior to" [preceeding]
A few misspellings have been corrected.
Dissertations at the Faculty of Medicine, NTNU

1977
Knut Joachim Berg: EFFECT OF ACETYLSALICYLIC ACID ON RENAL FUNCTION Karl Erik Viken and Arne Ødegaard: STUDIES ON HUMAN MONOCYTES CULTURED INVITRO Karel Bjørn Cyvin: CONGENITAL DISLOCATION OF THE HIP JOINT. Alf O. Brubakk: METHODS FOR STUDYING FLOW DYNAMICS IN THE LEFT VENTRICLE AND THE AORTA IN MAN. Geirmund Unsgaard: CYTOSTATIC AND IMMUNOREGULATORY ABILITIES OF HUMAN BLOOD MONOCYTES CULTURED IN VITRO Størker Jørstad: URAEMIC TOXINS Arne Olav Jenssen: SOME RHEOLOGICAL, CHEMICAL AND STRUCTURAL PROPERTIES OF MUCOID SPUTUM FROM PATIENTS WITH CHRONIC OBSTRUCTIVE BRONCHITIS 8. Jens Hammerstrøm: CYTOSTATIC AND CYTOLYTIC ACTIVITY OF HUMAN MONOCYTES AND EFFUSION MACROPHAGES AGAINST TUMOR CELLS IN VITRO Tore Syversen: EFFECTS OF METHYLMERCURY ON RAT BRAIN PROTEIN. 10. Torbjørn Iversen: SQUAMOUS CELL CARCINOMA OF THE VULVA. 11. Tor-Erik Widerøe: ASPECTS OF CONTINUOUS AMBULATORY PERITONEAL 12. Anton Hole: ALTERATIONS OF MONOCYTE AND LYMPHOCYTE FUNCTIONS IN REALTION TO SURGERY UNDER EPIDURAL OR GENERAL ANAESTHESIA. 13. Terje Terjesen: FRACTURE HEALING AND STRESS-PROTECTION AFTER METAL PLATE FIXATION AND EXTERNAL FIXATION. 14. Carsten Saunte: CLUSTER HEADACHE SYNDROME. 15. Inggard Lereim: TRAFFIC ACCIDENTS AND THEIR CONSEQUENCES. 16. Bjørn Magne Eggen: STUDIES IN CYTOTOXICITY IN HUMAN ADHERENT MONONUCLEAR BLOOD CELLS. 17. Trond Haug: FACTORS REGULATING BEHAVIORAL EFFECTS OG DRUGS. 18. Sven Erik Gisvold: RESUSCITATION AFTER COMPLETE GLOBAL BRAIN ISCHEMIA. 19. Terje Espevik: THE CYTOSKELETON OF HUMAN MONOCYTES. 20. Lars Bevanger: STUDIES OF THE Ibc (c) PROTEIN ANTIGENS OF GROUP B 21. Ole-Jan Iversen: RETROVIRUS-LIKE PARTICLES IN THE PATHOGENESIS OF 22. Lasse Eriksen: EVALUATION AND TREATMENT OF ALCOHOL DEPENDENT 23. Per I. Lundmo: ANDROGEN METABOLISM IN THE PROSTATE. 24. Dagfinn Berntzen: ANALYSIS AND MANAGEMENT OF EXPERIMENTAL AND 25. Odd Arnold Kildahl-Andersen: PRODUCTION AND CHARACTERIZATION OF MONOCYTE-DERIVED CYTOTOXIN AND ITS ROLE IN MONOCYTE-MEDIATED CYTOTOXICITY. 26. Ola Dale: VOLATILE ANAESTHETICS. 27. Per Martin Kleveland: STUDIES ON GASTRIN. 28. Audun N. Øksendal: THE CALCIUM PARADOX AND THE HEART. 29. Vilhjalmur R. Finsen: HIP FRACTURES 30. Rigmor Austgulen: TUMOR NECROSIS FACTOR: A MONOCYTE-DERIVED REGULATOR OF CELLULAR GROWTH. 31. Tom-Harald Edna: HEAD INJURIES ADMITTED TO HOSPITAL. 32. Joseph D. Borsi: NEW ASPECTS OF THE CLINICAL PHARMACOKINETICS OF 33. Olav F. M. Sellevold: GLUCOCORTICOIDS IN MYOCARDIAL PROTECTION. 34. Terje Skjærpe: NONINVASIVE QUANTITATION OF GLOBAL PARAMETERS ON LEFT VENTRICULAR FUNCTION: THE SYSTOLIC PULMONARY ARTERY PRESSURE AND CARDIAC OUTPUT. 35. Eyvind Rødahl: STUDIES OF IMMUNE COMPLEXES AND RETROVIRUS-LIKE ANTIGENS IN PATIENTS WITH ANKYLOSING SPONDYLITIS. 36. Ketil Thorstensen: STUDIES ON THE MECHANISMS OF CELLULAR UPTAKE OF IRON FROM TRANSFERRIN. 37. Anna Midelfart: STUDIES OF THE MECHANISMS OF ION AND FLUID TRANSPORT IN THE BOVINE CORNEA. 38. Eirik Helseth: GROWTH AND PLASMINOGEN ACTIVATOR ACTIVITY OF HUMAN GLIOMAS AND BRAIN METASTASES - WITH SPECIAL REFERENCE TO TRANSFORMING GROWTH FACTOR BETA AND THE EPIDERMAL GROWTH FACTOR RECEPTOR. 39. Petter C. Borchgrevink: MAGNESIUM AND THE ISCHEMIC HEART. 40. Kjell-Arne Rein: THE EFFECT OF EXTRACORPOREAL CIRCULATION ON SUBCUTANEOUS TRANSCAPILLARY FLUID BALANCE. 41. Arne Kristian Sandvik: RAT GASTRIC HISTAMINE. 42. Carl Bredo Dahl: ANIMAL MODELS IN PSYCHIATRY. 43. Torbjørn A. Fredriksen: CERVICOGENIC HEADACHE. 44. Rolf A. Walstad: CEFTAZIDIME. 45. Rolf Salvesen: THE PUPIL IN CLUSTER HEADACHE. 46. Nils Petter Jørgensen: DRUG EXPOSURE IN EARLY PREGNANCY. 47. Johan C. Ræder: PREMEDICATION AND GENERAL ANAESTHESIA IN OUTPATIENT GYNECOLOGICAL SURGERY. 48. M. R. Shalaby: IMMUNOREGULATORY PROPERTIES OF TNF-α AND THE RELATED 49. Anders Waage: THE COMPLEX PATTERN OF CYTOKINES IN SEPTIC SHOCK. 50. Bjarne Christian Eriksen: ELECTROSTIMULATION OF THE PELVIC FLOOR IN FEMALE URINARY INCONTINENCE. 51. Tore B. Halvorsen: PROGNOSTIC FACTORS IN COLORECTAL CANCER. 52. Asbjørn Nordby: CELLULAR TOXICITY OF ROENTGEN CONTRAST MEDIA. 53. Kåre E. Tvedt: X-RAY MICROANALYSIS OF BIOLOGICAL MATERIAL. 54. Tore C. Stiles: COGNITIVE VULNERABILITY FACTORS IN THE DEVELOPMENT AND MAINTENANCE OF DEPRESSION. 55. Eva Hofsli: TUMOR NECROSIS FACTOR AND MULTIDRUG RESISTANCE. 56. Helge S. Haarstad: TROPHIC EFFECTS OF CHOLECYSTOKININ AND SECRETIN ON THE RAT PANCREAS. 57. Lars Engebretsen: TREATMENT OF ACUTE ANTERIOR CRUCIATE LIGAMENT 58. Tarjei Rygnestad: DELIBERATE SELF-POISONING IN TRONDHEIM. 59. Arne Z. Henriksen: STUDIES ON CONSERVED ANTIGENIC DOMAINS ON MAJOR OUTER MEMBRANE PROTEINS FROM ENTEROBACTERIA. 60. Steinar Westin: UNEMPLOYMENT AND HEALTH: Medical and social consequences of a factory closure in a ten-year controlled follow-up study. 61. Ylva Sahlin: INJURY REGISTRATION, a tool for accident preventive work. 62. Helge Bjørnstad Pettersen: BIOSYNTHESIS OF COMPLEMENT BY HUMAN ALVEOLAR MACROPHAGES WITH SPECIAL REFERENCE TO SARCOIDOSIS. 63. Berit Schei: TRAPPED IN PAINFUL LOVE. 64. Lars J. Vatten: PROSPECTIVE STUDIES OF THE RISK OF BREAST CANCER IN A COHORT OF NORWEGIAN WOMAN. 65. Kåre Bergh: APPLICATIONS OF ANTI-C5a SPECIFIC MONOCLONAL ANTIBODIES FOR THE ASSESSMENT OF COMPLEMENT ACTIVATION. 66. Svein Svenningsen: THE CLINICAL SIGNIFICANCE OF INCREASED FEMORAL 67. Olbjørn Klepp: NONSEMINOMATOUS GERM CELL TESTIS CANCER: THERAPEUTIC OUTCOME AND PROGNOSTIC FACTORS. 68. Trond Sand: THE EFFECTS OF CLICK POLARITY ON BRAINSTEM AUDITORY EVOKED POTENTIALS AMPLITUDE, DISPERSION, AND LATENCY VARIABLES. 69. Kjetil B. Åsbakk: STUDIES OF A PROTEIN FROM PSORIATIC SCALE, PSO P27, WITH RESPECT TO ITS POTENTIAL ROLE IN IMMUNE REACTIONS IN PSORIASIS. 70. Arnulf Hestnes: STUDIES ON DOWN´S SYNDROME. 71. Randi Nygaard: LONG-TERM SURVIVAL IN CHILDHOOD LEUKEMIA. 72. Bjørn Hagen: THIO-TEPA. 73. Svein Anda: EVALUATION OF THE HIP JOINT BY COMPUTED TOMOGRAMPHY AND ULTRASONOGRAPHY. 74. Martin Svartberg: AN INVESTIGATION OF PROCESS AND OUTCOME OF SHORT-TERM PSYCHODYNAMIC PSYCHOTHERAPY. 75. Stig Arild Slørdahl: AORTIC REGURGITATION. 76. Harold C Sexton: STUDIES RELATING TO THE TREATMENT OF SYMPTOMATIC NON- PSYCHOTIC PATIENTS. 77. Maurice B. Vincent: VASOACTIVE PEPTIDES IN THE OCULAR/FOREHEAD AREA. 78. Terje Johannessen: CONTROLLED TRIALS IN SINGLE SUBJECTS. 79. Turid Nilsen: PYROPHOSPHATE IN HEPATOCYTE IRON METABOLISM. 80. Olav Haraldseth: NMR SPECTROSCOPY OF CEREBRAL ISCHEMIA AND REPERFUSION 81. Eiliv Brenna: REGULATION OF FUNCTION AND GROWTH OF THE OXYNTIC 82. Gunnar Bovim: CERVICOGENIC HEADACHE. 83. Jarl Arne Kahn: ASSISTED PROCREATION. 84. Bjørn Naume: IMMUNOREGULATORY EFFECTS OF CYTOKINES ON NK CELLS. 85. Rune Wiseth: AORTIC VALVE REPLACEMENT. 86. Jie Ming Shen: BLOOD FLOW VELOCITY AND RESPIRATORY STUDIES. 87. Piotr Kruszewski: SUNCT SYNDROME WITH SPECIAL REFERENCE TO THE AUTONOMIC NERVOUS SYSTEM. 88. Mette Haase Moen: ENDOMETRIOSIS. 89. Anne Vik: VASCULAR GAS EMBOLISM DURING AIR INFUSION AND AFTER DECOMPRESSION IN PIGS. 90. Lars Jacob Stovner: THE CHIARI TYPE I MALFORMATION. 91. Kjell Å. Salvesen: ROUTINE ULTRASONOGRAPHY IN UTERO AND DEVELOPMENT IN 92. Nina-Beate Liabakk: DEVELOPMENT OF IMMUNOASSAYS FOR TNF AND ITS SOLUBLE RECEPTORS. 93. Sverre Helge Torp: erbB ONCOGENES IN HUMAN GLIOMAS AND MENINGIOMAS. 94. Olav M. Linaker: MENTAL RETARDATION AND PSYCHIATRY. Past and present. 95. Per Oscar Feet: INCREASED ANTIDEPRESSANT AND ANTIPANIC EFFECT IN COMBINED TREATMENT WITH DIXYRAZINE AND TRICYCLIC ANTIDEPRESSANTS. 96. Stein Olav Samstad: CROSS SECTIONAL FLOW VELOCITY PROFILES FROM TWO- DIMENSIONAL DOPPLER ULTRASOUND: Studies on early mitral blood flow. 97. Bjørn Backe: STUDIES IN ANTENATAL CARE. 98. Gerd Inger Ringdal: QUALITY OF LIFE IN CANCER PATIENTS. 99. Torvid Kiserud: THE DUCTUS VENOSUS IN THE HUMAN FETUS. 100.Hans E. Fjøsne: HORMONAL REGULATION OF PROSTATIC METABOLISM. 101.Eylert Brodtkorb: CLINICAL ASPECTS OF EPILEPSY IN THE MENTALLY RETARDED. 102.Roar Juul: PEPTIDERGIC MECHANISMS IN HUMAN SUBARACHNOID HEMORRHAGE. 103.Unni Syversen: CHROMOGRANIN A. Phsysiological and Clinical Role. 104.Odd Gunnar Brakstad: THERMOSTABLE NUCLEASE AND THE nuc GENE IN THE DIAGNOSIS OF Staphylococcus aureus INFECTIONS. 105.Terje Engan: NUCLEAR MAGNETIC RESONANCE (NMR) SPECTROSCOPY OF PLASMA IN MALIGNANT DISEASE. 106.Kirsten Rasmussen: VIOLENCE IN THE MENTALLY DISORDERED. 107.Finn Egil Skjeldestad: INDUCED ABORTION: Timetrends and Determinants. 108.Roar Stenseth: THORACIC EPIDURAL ANALGESIA IN AORTOCORONARY BYPASS 109.Arild Faxvaag: STUDIES OF IMMUNE CELL FUNCTION in mice infected with MURINE 110.Svend Aakhus: NONINVASIVE COMPUTERIZED ASSESSMENT OF LEFT VENTRICULAR FUNCTION AND SYSTEMIC ARTERIAL PROPERTIES. Methodology and some clinical applications. 111.Klaus-Dieter Bolz: INTRAVASCULAR ULTRASONOGRAPHY. 112.Petter Aadahl: CARDIOVASCULAR EFFECTS OF THORACIC AORTIC CROSS- 113.Sigurd Steinshamn: CYTOKINE MEDIATORS DURING GRANULOCYTOPENIC 114.Hans Stifoss-Hanssen: SEEKING MEANING OR HAPPINESS? 115.Anne Kvikstad: LIFE CHANGE EVENTS AND MARITAL STATUS IN RELATION TO RISK AND PROGNOSIS OF CANCER. 116.Torbjørn Grøntvedt: TREATMENT OF ACUTE AND CHRONIC ANTERIOR CRUCIATE LIGAMENT INJURIES. A clinical and biomechanical study. 117.Sigrid Hørven Wigers: CLINICAL STUDIES OF FIBROMYALGIA WITH FOCUS ON ETIOLOGY, TREATMENT AND OUTCOME. 118.Jan Schjøtt: MYOCARDIAL PROTECTION: Functional and Metabolic Characteristics of Two Endogenous Protective Principles. 119.Marit Martinussen: STUDIES OF INTESTINAL BLOOD FLOW AND ITS RELATION TO TRANSITIONAL CIRCULATORY ADAPATION IN NEWBORN INFANTS. 120.Tomm B. Müller: MAGNETIC RESONANCE IMAGING IN FOCAL CEREBRAL 121.Rune Haaverstad: OEDEMA FORMATION OF THE LOWER EXTREMITIES. 122.Magne Børset: THE ROLE OF CYTOKINES IN MULTIPLE MYELOMA, WITH SPECIAL REFERENCE TO HEPATOCYTE GROWTH FACTOR. 123.Geir Smedslund: A THEORETICAL AND EMPIRICAL INVESTIGATION OF SMOKING, STRESS AND DISEASE: RESULTS FROM A POPULATION SURVEY. 124.Torstein Vik: GROWTH, MORBIDITY, AND PSYCHOMOTOR DEVELOPMENT IN INFANTS WHO WERE GROWTH RETARDED IN UTERO. 125.Siri Forsmo: ASPECTS AND CONSEQUENCES OF OPPORTUNISTIC SCREENING FOR CERVICAL CANCER. Results based on data from three Norwegian counties. 126.Jon S. Skranes: CEREBRAL MRI AND NEURODEVELOPMENTAL OUTCOME IN VERY LOW BIRTH WEIGHT (VLBW) CHILDREN. A follow-up study of a geographically based year cohort of VLBW children at ages one and six years. 127.Knut Bjørnstad: COMPUTERIZED ECHOCARDIOGRAPHY FOR EVALUTION OF CORONARY ARTERY DISEASE. 128.Grethe Elisabeth Borchgrevink: DIAGNOSIS AND TREATMENT OF WHIPLASH/NECK SPRAIN INJURIES CAUSED BY CAR ACCIDENTS. 129.Tor Elsås: NEUROPEPTIDES AND NITRIC OXIDE SYNTHASE IN OCULAR AUTONOMIC AND SENSORY NERVES. 130.Rolf W. Gråwe: EPIDEMIOLOGICAL AND NEUROPSYCHOLOGICAL PERSPECTIVES ON SCHIZOPHRENIA. 131.Tonje Strømholm: CEREBRAL HAEMODYNAMICS DURING THORACIC AORTIC CROSSCLAMPING. An experimental study in pigs. 132.Martinus Bråten: STUDIES ON SOME PROBLEMS REALTED TO INTRAMEDULLARY NAILING OF FEMORAL FRACTURES. 133.Ståle Nordgård: PROLIFERATIVE ACTIVITY AND DNA CONTENT AS PROGNOSTIC INDICATORS IN ADENOID CYSTIC CARCINOMA OF THE HEAD AND NECK. 134.Egil Lien: SOLUBLE RECEPTORS FOR TNF AND LPS: RELEASE PATTERN AND
POSSIBLE SIGNIFICANCE IN DISEASE. 135.Marit Bjørgaas: HYPOGLYCAEMIA IN CHILDREN WITH DIABETES MELLITUS 136.Frank Skorpen: GENETIC AND FUNCTIONAL ANALYSES OF DNA REPAIR IN HUMAN 137.Juan A. Pareja: SUNCT SYNDROME. ON THE CLINICAL PICTURE. ITS DISTINCTION FROM OTHER, SIMILAR HEADACHES. 138.Anders Angelsen: NEUROENDOCRINE CELLS IN HUMAN PROSTATIC CARCINOMAS AND THE PROSTATIC COMPLEX OF RAT, GUINEA PIG, CAT AND DOG. 139.Fabio Antonaci: CHRONIC PAROXYSMAL HEMICRANIA AND HEMICRANIA CONTINUA: TWO DIFFERENT ENTITIES? 140.Sven M. Carlsen: ENDOCRINE AND METABOLIC EFFECTS OF METFORMIN WITH SPECIAL EMPHASIS ON CARDIOVASCULAR RISK FACTORES. 141.Terje A. Murberg: DEPRESSIVE SYMPTOMS AND COPING AMONG PATIENTS WITH CONGESTIVE HEART FAILURE. 142.Harm-Gerd Karl Blaas: THE EMBRYONIC EXAMINATION. Ultrasound studies on the development of the human embryo. 143.Noèmi Becser Andersen:THE CEPHALIC SENSORY NERVES IN UNILATERAL HEADACHES. Anatomical background and neurophysiological evaluation. 144.Eli-Janne Fiskerstrand: LASER TREATMENT OF PORT WINE STAINS. A study of the efficacy and limitations of the pulsed dye laser. Clinical and morfological analyses aimed at improving the therapeutic outcome. 145.Bård Kulseng: A STUDY OF ALGINATE CAPSULE PROPERTIES AND CYTOKINES IN RELATION TO INSULIN DEPENDENT DIABETES MELLITUS. 146.Terje Haug: STRUCTURE AND REGULATION OF THE HUMAN UNG GENE ENCODING URACIL-DNA GLYCOSYLASE. 147.Heidi Brurok: MANGANESE AND THE HEART. A Magic Metal with Diagnostic and Therapeutic Possibilites. 148.Agnes Kathrine Lie: DIAGNOSIS AND PREVALENCE OF HUMAN PAPILLOMAVIRUS INFECTION IN CERVICAL INTRAEPITELIAL NEOPLASIA. Relationship to Cell Cycle Regulatory Proteins and HLA DQBI Genes. 149.Ronald Mårvik: PHARMACOLOGICAL, PHYSIOLOGICAL AND PATHOPHYSIOLOGICAL STUDIES ON ISOLATED STOMACS. 150.Ketil Jarl Holen: THE ROLE OF ULTRASONOGRAPHY IN THE DIAGNOSIS AND TREATMENT OF HIP DYSPLASIA IN NEWBORNS. 151.Irene Hetlevik: THE ROLE OF CLINICAL GUIDELINES IN CARDIOVASCULAR RISK INTERVENTION IN GENERAL PRACTICE. 152.Katarina Tunòn: ULTRASOUND AND PREDICTION OF GESTATIONAL AGE. 153.Johannes Soma: INTERACTION BETWEEN THE LEFT VENTRICLE AND THE SYSTEMIC 154.Arild Aamodt: DEVELOPMENT AND PRE-CLINICAL EVALUATION OF A CUSTOM- MADE FEMORAL STEM. 155.Agnar Tegnander: DIAGNOSIS AND FOLLOW-UP OF CHILDREN WITH SUSPECTED OR KNOWN HIP DYSPLASIA. 156.Bent Indredavik: STROKE UNIT TREATMENT: SHORT AND LONG-TERM EFFECTS 157.Jolanta Vanagaite Vingen: PHOTOPHOBIA AND PHONOPHOBIA IN PRIMARY 158.Ola Dalsegg Sæther: PATHOPHYSIOLOGY DURING PROXIMAL AORTIC CROSS- CLAMPING CLINICAL AND EXPERIMENTAL STUDIES 159.xxxxxxxxx (blind number) 160.Christina Vogt Isaksen: PRENATAL ULTRASOUND AND POSTMORTEM FINDINGS – A TEN YEAR CORRELATIVE STUDY OF FETUSES AND INFANTS WITH DEVELOPMENTAL ANOMALIES. 161.Holger Seidel: HIGH-DOSE METHOTREXATE THERAPY IN CHILDREN WITH ACUTE LYMPHOCYTIC LEUKEMIA: DOSE, CONCENTRATION, AND EFFECT CONSIDERATIONS. 162.Stein Hallan: IMPLEMENTATION OF MODERN MEDICAL DECISION ANALYSIS INTO CLINICAL DIAGNOSIS AND TREATMENT. 163.Malcolm Sue-Chu: INVASIVE AND NON-INVASIVE STUDIES IN CROSS-COUNTRY SKIERS WITH ASTHMA-LIKE SYMPTOMS. 164.Ole-Lars Brekke: EFFECTS OF ANTIOXIDANTS AND FATTY ACIDS ON TUMOR NECROSIS FACTOR-INDUCED CYTOTOXICITY. 165.Jan Lundbom: AORTOCORONARY BYPASS SURGERY: CLINICAL ASPECTS, COST CONSIDERATIONS AND WORKING ABILITY. 166.John-Anker Zwart: LUMBAR NERVE ROOT COMPRESSION, BIOCHEMICAL AND NEUROPHYSIOLOGICAL ASPECTS. 167.Geir Falck: HYPEROSMOLALITY AND THE HEART. 168.Eirik Skogvoll: CARDIAC ARREST Incidence, Intervention and Outcome. 169.Dalius Bansevicius: SHOULDER-NECK REGION IN CERTAIN HEADACHES AND CHRONIC PAIN SYNDROMES. 170.Bettina Kinge: REFRACTIVE ERRORS AND BIOMETRIC CHANGES AMONG UNIVERSITY STUDENTS IN NORWAY. 171.Gunnar Qvigstad: CONSEQUENCES OF HYPERGASTRINEMIA IN MAN 172.Hanne Ellekjær: EPIDEMIOLOGICAL STUDIES OF STROKE IN A NORWEGIAN POPULATION. INCIDENCE, RISK FACTORS AND PROGNOSIS 173.Hilde Grimstad: VIOLENCE AGAINST WOMEN AND PREGNANCY OUTCOME. 174.Astrid Hjelde: SURFACE TENSION AND COMPLEMENT ACTIVATION: Factors influencing bubble formation and bubble effects after decompression. 175.Kjell A. Kvistad: MR IN BREAST CANCER – A CLINICAL STUDY. 176.Ivar Rossvoll: ELECTIVE ORTHOPAEDIC SURGERY IN A DEFINED POPULATION. Studies on demand, waiting time for treatment and incapacity for work. 177.Carina Seidel: PROGNOSTIC VALUE AND BIOLOGICAL EFFECTS OF HEPATOCYTE GROWTH FACTOR AND SYNDECAN-1 IN MULTIPLE MYELOMA. 178.Alexander Wahba: THE INFLUENCE OF CARDIOPULMONARY BYPASS ON PLATELET FUNCTION AND BLOOD COAGULATION – DETERMINANTS AND CLINICAL CONSEQUENSES 179.Marcus Schmitt-Egenolf: THE RELEVANCE OF THE MAJOR hISTOCOMPATIBILITY COMPLEX FOR THE GENETICS OF PSORIASIS 180.Odrun Arna Gederaas: BIOLOGICAL MECHANISMS INVOLVED IN 5-AMINOLEVULINIC ACID BASED PHOTODYNAMIC THERAPY 181.Pål Richard Romundstad: CANCER INCIDENCE AMONG NORWEGIAN ALUMINIUM 182.Henrik Hjorth-Hansen: NOVEL CYTOKINES IN GROWTH CONTROL AND BONE DISEASE OF MULTIPLE MYELOMA 183.Gunnar Morken: SEASONAL VARIATION OF HUMAN MOOD AND BEHAVIOUR 184.Bjørn Olav Haugen: MEASUREMENT OF CARDIAC OUTPUT AND STUDIES OF VELOCITY PROFILES IN AORTIC AND MITRAL FLOW USING TWO- AND THREE-DIMENSIONAL COLOUR FLOW IMAGING 185.Geir Bråthen: THE CLASSIFICATION AND CLINICAL DIAGNOSIS OF ALCOHOL- RELATED SEIZURES 186.Knut Ivar Aasarød: RENAL INVOLVEMENT IN INFLAMMATORY RHEUMATIC DISEASE. A Study of Renal Disease in Wegener's Granulomatosis and in Primary Sjögren's Syndrome 187.Trude Helen Flo: RESEPTORS INVOLVED IN CELL ACTIVATION BY DEFINED URONIC ACID POLYMERS AND BACTERIAL COMPONENTS 188.Bodil Kavli: HUMAN URACIL-DNA GLYCOSYLASES FROM THE UNG GENE: STRUCTRUAL BASIS FOR SUBSTRATE SPECIFICITY AND REPAIR 189.Liv Thommesen: MOLECULAR MECHANISMS INVOLVED IN TNF- AND GASTRIN- MEDIATED GENE REGULATION 190.Turid Lingaas Holmen: SMOKING AND HEALTH IN ADOLESCENCE; THE NORD- TRØNDELAG HEALTH STUDY, 1995-97 191.Øyvind Hjertner: MULTIPLE MYELOMA: INTERACTIONS BETWEEN MALIGNANT PLASMA CELLS AND THE BONE MICROENVIRONMENT 192.Asbjørn Støylen: STRAIN RATE IMAGING OF THE LEFT VENTRICLE BY ULTRASOUND. FEASIBILITY, CLINICAL VALIDATION AND PHYSIOLOGICAL ASPECTS 193.Kristian Midthjell: DIABETES IN ADULTS IN NORD-TRØNDELAG. PUBLIC HEALTH ASPECTS OF DIABETES MELLITUS IN A LARGE, NON-SELECTED NORWEGIAN POPULATION. 194.Guanglin Cui: FUNCTIONAL ASPECTS OF THE ECL CELL IN RODENTS 195.Ulrik Wisløff: CARDIAC EFFECTS OF AEROBIC ENDURANCE TRAINING: HYPERTROPHY, CONTRACTILITY AND CALCUIM HANDLING IN NORMAL AND FAILING HEART 196.Øyvind Halaas: MECHANISMS OF IMMUNOMODULATION AND CELL-MEDIATED CYTOTOXICITY INDUCED BY BACTERIAL PRODUCTS 197.Tore Amundsen: PERFUSION MR IMAGING IN THE DIAGNOSIS OF PULMONARY 198.Nanna Kurtze: THE SIGNIFICANCE OF ANXIETY AND DEPRESSION IN FATIQUE AND PATTERNS OF PAIN AMONG INDIVIDUALS DIAGNOSED WITH FIBROMYALGIA: RELATIONS WITH QUALITY OF LIFE, FUNCTIONAL DISABILITY, LIFESTYLE, EMPLOYMENT STATUS, CO-MORBIDITY AND GENDER 199.Tom Ivar Lund Nilsen: PROSPECTIVE STUDIES OF CANCER RISK IN NORD- TRØNDELAG: THE HUNT STUDY. Associations with anthropometric, socioeconomic, and lifestyle risk factors 200.Asta Kristine Håberg: A NEW APPROACH TO THE STUDY OF MIDDLE CEREBRAL ARTERY OCCLUSION IN THE RAT USING MAGNETIC RESONANCE TECHNIQUES 201.Knut Jørgen Arntzen: PREGNANCY AND CYTOKINES 202.Henrik Døllner: INFLAMMATORY MEDIATORS IN PERINATAL INFECTIONS 203.Asta Bye: LOW FAT, LOW LACTOSE DIET USED AS PROPHYLACTIC TREATMENT OF ACUTE INTESTINAL REACTIONS DURING PELVIC RADIOTHERAPY. A PROSPECTIVE RANDOMISED STUDY. 204.Sylvester Moyo: STUDIES ON STREPTOCOCCUS AGALACTIAE (GROUP B STREPTOCOCCUS) SURFACE-ANCHORED MARKERS WITH EMPHASIS ON STRAINS AND HUMAN SERA FROM ZIMBABWE. 205.Knut Hagen: HEAD-HUNT: THE EPIDEMIOLOGY OF HEADACHE IN NORD- 206.Li Lixin: ON THE REGULATION AND ROLE OF UNCOUPLING PROTEIN-2 IN INSULIN PRODUCING ß-CELLS 207.Anne Hildur Henriksen: SYMPTOMS OF ALLERGY AND ASTHMA VERSUS MARKERS OF LOWER AIRWAY INFLAMMATION AMONG ADOLESCENTS 208.Egil Andreas Fors: NON-MALIGNANT PAIN IN RELATION TO PSYCHOLOGICAL AND ENVIRONTENTAL FACTORS. EXPERIENTAL AND CLINICAL STUDES OF PAIN WITH FOCUS ON FIBROMYALGIA 209.Pål Klepstad: MORPHINE FOR CANCER PAIN 210.Ingunn Bakke: MECHANISMS AND CONSEQUENCES OF PEROXISOME PROLIFERATOR-INDUCED HYPERFUNCTION OF THE RAT GASTRIN PRODUCING CELL 211.Ingrid Susann Gribbestad: MAGNETIC RESONANCE IMAGING AND SPECTROSCOPY OF 212.Rønnaug Astri Ødegård: PREECLAMPSIA – MATERNAL RISK FACTORS AND FETAL 213.Johan Haux: STUDIES ON CYTOTOXICITY INDUCED BY HUMAN NATURAL KILLER CELLS AND DIGITOXIN 214.Turid Suzanne Berg-Nielsen: PARENTING PRACTICES AND MENTALLY DISORDERED 215.Astrid Rydning: BLOOD FLOW AS A PROTECTIVE FACTOR FOR THE STOMACH MUCOSA. AN EXPERIMENTAL STUDY ON THE ROLE OF MAST CELLS AND SENSORY AFFERENT NEURONS 216.Jan Pål Loennechen: HEART FAILURE AFTER MYOCARDIAL INFARCTION. Regional Differences, Myocyte Function, Gene Expression, and Response to Cariporide, Losartan, and Exercise Training. 217.Elisabeth Qvigstad: EFFECTS OF FATTY ACIDS AND OVER-STIMULATION ON INSULIN SECRETION IN MAN 218.Arne Åsberg: EPIDEMIOLOGICAL STUDIES IN HEREDITARY HEMOCHROMATOSIS: PREVALENCE, MORBIDITY AND BENEFIT OF SCREENING. 219.Johan Fredrik Skomsvoll: REPRODUCTIVE OUTCOME IN WOMEN WITH RHEUMATIC DISEASE. A population registry based study of the effects of inflammatory rheumatic disease and connective tissue disease on reproductive outcome in Norwegian women in 1967-1995. 220.Siv Mørkved: URINARY INCONTINENCE DURING PREGNANCY AND AFTER DELIVERY: EFFECT OF PELVIC FLOOR MUSCLE TRAINING IN PREVENTION AND TREATMENT 221.Marit S. Jordhøy: THE IMPACT OF COMPREHENSIVE PALLIATIVE CARE 222.Tom Christian Martinsen: HYPERGASTRINEMIA AND HYPOACIDITY IN RODENTS – CAUSES AND CONSEQUENCES 223.Solveig Tingulstad: CENTRALIZATION OF PRIMARY SURGERY FOR OVARAIN CANCER. FEASIBILITY AND IMPACT ON SURVIVAL 224.Haytham Eloqayli: METABOLIC CHANGES IN THE BRAIN CAUSED BY EPILEPTIC 225.Torunn Bruland: STUDIES OF EARLY RETROVIRUS-HOST INTERACTIONS – VIRAL DETERMINANTS FOR PATHOGENESIS AND THE INFLUENCE OF SEX ON THE SUSCEPTIBILITY TO FRIEND MURINE LEUKAEMIA VIRUS INFECTION 226.Torstein Hole: DOPPLER ECHOCARDIOGRAPHIC EVALUATION OF LEFT VENTRICULAR FUNCTION IN PATIENTS WITH ACUTE MYOCARDIAL INFARCTION 227.Vibeke Nossum: THE EFFECT OF VASCULAR BUBBLES ON ENDOTHELIAL FUNCTION 228.Sigurd Fasting: ROUTINE BASED RECORDING OF ADVERSE EVENTS DURING ANAESTHESIA – APPLICATION IN QUALITY IMPROVEMENT AND SAFETY 229.Solfrid Romundstad: EPIDEMIOLOGICAL STUDIES OF MICROALBUMINURIA. THE NORD-TRØNDELAG HEALTH STUDY 1995-97 (HUNT 2) 230.Geir Torheim: PROCESSING OF DYNAMIC DATA SETS IN MAGNETIC RESONANCE 231.Catrine Ahlén: SKIN INFECTIONS IN OCCUPATIONAL SATURATION DIVERS IN THE NORTH SEA AND THE IMPACT OF THE ENVIRONMENT 232.Arnulf Langhammer: RESPIRATORY SYMPTOMS, LUNG FUNCTION AND BONE MINERAL DENSITY IN A COMPREHENSIVE POPULATION SURVEY. THE NORD-TRØNDELAG HEALTH STUDY 1995-97. THE BRONCHIAL OBSTRUCTION IN NORD-TRØNDELAG STUDY 233.Einar Kjelsås: EATING DISORDERS AND PHYSICAL ACTIVITY IN NON-CLINICAL 234.Arne Wibe: RECTAL CANCER TREATMENT IN NORWAY – STANDARDISATION OF SURGERY AND QUALITY ASSURANCE 235.Eivind Witsø: BONE GRAFT AS AN ANTIBIOTIC CARRIER 236.Anne Mari Sund: DEVELOPMENT OF DEPRESSIVE SYMPTOMS IN EARLY 237.Hallvard Lærum: EVALUATION OF ELECTRONIC MEDICAL RECORDS – A CLINICAL TASK PERSPECTIVE 238.Gustav Mikkelsen: ACCESSIBILITY OF INFORMATION IN ELECTRONIC PATIENT RECORDS; AN EVALUATION OF THE ROLE OF DATA QUALITY 239.Steinar Krokstad: SOCIOECONOMIC INEQUALITIES IN HEALTH AND DISABILITY. SOCIAL EPIDEMIOLOGY IN THE NORD-TRØNDELAG HEALTH STUDY (HUNT), NORWAY 240.Arne Kristian Myhre: NORMAL VARIATION IN ANOGENITAL ANATOMY AND MICROBIOLOGY IN NON-ABUSED PRESCHOOL CHILDREN 241.Ingunn Dybedal: NEGATIVE REGULATORS OF HEMATOPOIETEC STEM AND PROGENITOR CELLS 242.Beate Sitter: TISSUE CHARACTERIZATION BY HIGH RESOLUTION MAGIC ANGLE SPINNING MR SPECTROSCOPY 243.Per Arne Aas: MACROMOLECULAR MAINTENANCE IN HUMAN CELLS – REPAIR OF URACIL IN DNA AND METHYLATIONS IN DNA AND RNA 244.Anna Bofin: FINE NEEDLE ASPIRATION CYTOLOGY IN THE PRIMARY INVESTIGATION OF BREAST TUMOURS AND IN THE DETERMINATION OF TREATMENT STRATEGIES 245.Jim Aage Nøttestad: DEINSTITUTIONALIZATION AND MENTAL HEALTH CHANGES AMONG PEOPLE WITH MENTAL RETARDATION 246.Reidar Fossmark: GASTRIC CANCER IN JAPANESE COTTON RATS 247.Wibeke Nordhøy: MANGANESE AND THE HEART, INTRACELLULAR MR RELAXATION AND WATER EXCHANGE ACROSS THE CARDIAC CELL MEMBRANE 248.Sturla Molden: QUANTITATIVE ANALYSES OF SINGLE UNITS RECORDED FROM THE HIPPOCAMPUS AND ENTORHINAL CORTEX OF BEHAVING RATS 249.Wenche Brenne Drøyvold: EPIDEMIOLOGICAL STUDIES ON WEIGHT CHANGE AND HEALTH IN A LARGE POPULATION. THE NORD-TRØNDELAG HEALTH STUDY (HUNT) 250.Ragnhild Støen: ENDOTHELIUM-DEPENDENT VASODILATION IN THE FEMORAL ARTERY OF DEVELOPING PIGLETS 251.Aslak Steinsbekk: HOMEOPATHY IN THE PREVENTION OF UPPER RESPIRATORY TRACT INFECTIONS IN CHILDREN 252.Hill-Aina Steffenach: MEMORY IN HIPPOCAMPAL AND CORTICO-HIPPOCAMPAL 253.Eystein Stordal: ASPECTS OF THE EPIDEMIOLOGY OF DEPRESSIONS BASED ON SELF-RATING IN A LARGE GENERAL HEALTH STUDY (THE HUNT-2 STUDY) 254.Viggo Pettersen: FROM MUSCLES TO SINGING: THE ACTIVITY OF ACCESSORY BREATHING MUSCLES AND THORAX MOVEMENT IN CLASSICAL SINGING 255.Marianne Fyhn: SPATIAL MAPS IN THE HIPPOCAMPUS AND ENTORHINAL CORTEX 256.Robert Valderhaug: OBSESSIVE-COMPULSIVE DISORDER AMONG CHILDREN AND ADOLESCENTS: CHARACTERISTICS AND PSYCHOLOGICAL MANAGEMENT OF PATIENTS IN OUTPATIENT PSYCHIATRIC CLINICS 257.Erik Skaaheim Haug: INFRARENAL ABDOMINAL AORTIC ANEURYSMS – COMORBIDITY AND RESULTS FOLLOWING OPEN SURGERY 258.Daniel Kondziella: GLIAL-NEURONAL INTERACTIONS IN EXPERIMENTAL BRAIN 259.Vegard Heimly Brun: ROUTES TO SPATIAL MEMORY IN HIPPOCAMPAL PLACE 260.Kenneth McMillan: PHYSIOLOGICAL ASSESSMENT AND TRAINING OF ENDURANCE AND STRENGTH IN PROFESSIONAL YOUTH SOCCER PLAYERS 261.Marit Sæbø Indredavik: MENTAL HEALTH AND CEREBRAL MAGNETIC RESONANCE IMAGING IN ADOLESCENTS WITH LOW BIRTH WEIGHT 262.Ole Johan Kemi: ON THE CELLULAR BASIS OF AEROBIC FITNESS, INTENSITY- DEPENDENCE AND TIME-COURSE OF CARDIOMYOCYTE AND ENDOTHELIAL ADAPTATIONS TO EXERCISE TRAINING 263.Eszter Vanky: POLYCYSTIC OVARY SYNDROME – METFORMIN TREATMENT IN 264.Hild Fjærtoft: EXTENDED STROKE UNIT SERVICE AND EARLY SUPPORTED DISCHARGE. SHORT AND LONG-TERM EFFECTS 265.Grete Dyb: POSTTRAUMATIC STRESS REACTIONS IN CHILDREN AND 266.Vidar Fykse: SOMATOSTATIN AND THE STOMACH 267.Kirsti Berg: OXIDATIVE STRESS AND THE ISCHEMIC HEART: A STUDY IN PATIENTS UNDERGOING CORONARY REVASCULARIZATION 268.Björn Inge Gustafsson: THE SEROTONIN PRODUCING ENTEROCHROMAFFIN CELL, AND EFFECTS OF HYPERSEROTONINEMIA ON HEART AND BONE 269.Torstein Baade Rø: EFFECTS OF BONE MORPHOGENETIC PROTEINS, HEPATOCYTE GROWTH FACTOR AND INTERLEUKIN-21 IN MULTIPLE MYELOMA 270.May-Britt Tessem: METABOLIC EFFECTS OF ULTRAVIOLET RADIATION ON THE ANTERIOR PART OF THE EYE 271.Anne-Sofie Helvik: COPING AND EVERYDAY LIFE IN A POPULATION OF ADULTS WITH HEARING IMPAIRMENT 272.Therese Standal: MULTIPLE MYELOMA: THE INTERPLAY BETWEEN MALIGNANT PLASMA CELLS AND THE BONE MARROW MICROENVIRONMENT 273.Ingvild Saltvedt: TREATMENT OF ACUTELY SICK, FRAIL ELDERLY PATIENTS IN A GERIATRIC EVALUATION AND MANAGEMENT UNIT – RESULTS FROM A PROSPECTIVE RANDOMISED TRIAL 274.Birger Henning Endreseth: STRATEGIES IN RECTAL CANCER TREATMENT – FOCUS ON EARLY RECTAL CANCER AND THE INFLUENCE OF AGE ON PROGNOSIS 275.Anne Mari Aukan Rokstad: ALGINATE CAPSULES AS BIOREACTORS FOR CELL 276.Mansour Akbari: HUMAN BASE EXCISION REPAIR FOR PRESERVATION OF GENOMIC 277.Stein Sundstrøm: IMPROVING TREATMENT IN PATIENTS WITH LUNG CANCER – RESULTS FROM TWO MULITCENTRE RANDOMISED STUDIES 278.Hilde Pleym: BLEEDING AFTER CORONARY ARTERY BYPASS SURGERY - STUDIES ON HEMOSTATIC MECHANISMS, PROPHYLACTIC DRUG TREATMENT AND EFFECTS OF AUTOTRANSFUSION 279.Line Merethe Oldervoll: PHYSICAL ACTIVITY AND EXERCISE INTERVENTIONS IN 280.Boye Welde: THE SIGNIFICANCE OF ENDURANCE TRAINING, RESISTANCE TRAINING AND MOTIVATIONAL STYLES IN ATHLETIC PERFORMANCE AMONG ELITE JUNIOR CROSS-COUNTRY SKIERS 281.Per Olav Vandvik: IRRITABLE BOWEL SYNDROME IN NORWAY, STUDIES OF PREVALENCE, DIAGNOSIS AND CHARACTERISTICS IN GENERAL PRACTICE AND IN THE POPULATION 282.Idar Kirkeby-Garstad: CLINICAL PHYSIOLOGY OF EARLY MOBILIZATION AFTER 283.Linn Getz: SUSTAINABLE AND RESPONSIBLE PREVENTIVE MEDICINE. CONCEPTUALISING ETHICAL DILEMMAS ARISING FROM CLINICAL IMPLEMENTATION OF ADVANCING MEDICAL TECHNOLOGY 284.Eva Tegnander: DETECTION OF CONGENITAL HEART DEFECTS IN A NON-SELECTED POPULATION OF 42,381 FETUSES 285.Kristin Gabestad Nørsett: GENE EXPRESSION STUDIES IN GASTROINTESTINAL PATHOPHYSIOLOGY AND NEOPLASIA 286.Per Magnus Haram: GENETIC VS. AQUIRED FITNESS: METABOLIC, VASCULAR AND CARDIOMYOCYTE ADAPTATIONS 287.Agneta Johansson: GENERAL RISK FACTORS FOR GAMBLING PROBLEMS AND THE PREVALENCE OF PATHOLOGICAL GAMBLING IN NORWAY 288.Svein Artur Jensen: THE PREVALENCE OF SYMPTOMATIC ARTERIAL DISEASE OF 289.Charlotte Björk Ingul: QUANITIFICATION OF REGIONAL MYOCARDIAL FUNCTION BY STRAIN RATE AND STRAIN FOR EVALUATION OF CORONARY ARTERY DISEASE. AUTOMATED VERSUS MANUAL ANALYSIS DURING ACUTE MYOCARDIAL INFARCTION AND DOBUTAMINE STRESS ECHOCARDIOGRAPHY 290.Jakob Nakling: RESULTS AND CONSEQUENCES OF ROUTINE ULTRASOUND SCREENING IN PREGNANCY – A GEOGRAPHIC BASED POPULATION STUDY 291.Anne Engum: DEPRESSION AND ANXIETY – THEIR RELATIONS TO THYROID DYSFUNCTION AND DIABETES IN A LARGE EPIDEMIOLOGICAL STUDY 292.Ottar Bjerkeset: ANXIETY AND DEPRESSION IN THE GENERAL POPULATION: RISK FACTORS, INTERVENTION AND OUTCOME – THE NORD-TRØNDELAG HEALTH STUDY (HUNT) 293.Jon Olav Drogset: RESULTS AFTER SURGICAL TREATMENT OF ANTERIOR CRUCIATE LIGAMENT INJURIES – A CLINICAL STUDY 294.Lars Fosse: MECHANICAL BEHAVIOUR OF COMPACTED MORSELLISED BONE – AN EXPERIMENTAL IN VITRO STUDY 295.Gunilla Klensmeden Fosse: MENTAL HEALTH OF PSYCHIATRIC OUTPATIENTS BULLIED IN CHILDHOOD 296.Paul Jarle Mork: MUSCLE ACTIVITY IN WORK AND LEISURE AND ITS ASSOCIATION TO MUSCULOSKELETAL PAIN 297.Björn Stenström: LESSONS FROM RODENTS: I: MECHANISMS OF OBESITY SURGERY – ROLE OF STOMACH. II: CARCINOGENIC EFFECTS OF HELICOBACTER PYLORI AND SNUS IN THE STOMACH 298.Haakon R. Skogseth: INVASIVE PROPERTIES OF CANCER – A TREATMENT TARGET ? IN VITRO STUDIES IN HUMAN PROSTATE CANCER CELL LINES 299.Janniche Hammer: GLUTAMATE METABOLISM AND CYCLING IN MESIAL TEMPORAL LOBE EPILEPSY 300.May Britt Drugli: YOUNG CHILDREN TREATED BECAUSE OF ODD/CD: CONDUCT PROBLEMS AND SOCIAL COMPETENCIES IN DAY-CARE AND SCHOOL SETTINGS 301.Arne Skjold: MAGNETIC RESONANCE KINETICS OF MANGANESE DIPYRIDOXYL DIPHOSPHATE (MnDPDP) IN HUMAN MYOCARDIUM. STUDIES IN HEALTHY VOLUNTEERS AND IN PATIENTS WITH RECENT MYOCARDIAL INFARCTION 302.Siri Malm: LEFT VENTRICULAR SYSTOLIC FUNCTION AND MYOCARDIAL PERFUSION ASSESSED BY CONTRAST ECHOCARDIOGRAPHY 303.Valentina Maria do Rosario Cabral Iversen: MENTAL HEALTH AND PSYCHOLOGICAL ADAPTATION OF CLINICAL AND NON-CLINICAL MIGRANT GROUPS 304.Lasse Løvstakken: SIGNAL PROCESSING IN DIAGNOSTIC ULTRASOUND: ALGORITHMS FOR REAL-TIME ESTIMATION AND VISUALIZATION OF BLOOD FLOW VELOCITY 305.Elisabeth Olstad: GLUTAMATE AND GABA: MAJOR PLAYERS IN NEURONAL 306.Lilian Leistad: THE ROLE OF CYTOKINES AND PHOSPHOLIPASE A s IN ARTICULAR CARTILAGE CHONDROCYTES IN RHEUMATOID ARTHRITIS AND OSTEOARTHRITIS 307.Arne Vaaler: EFFECTS OF PSYCHIATRIC INTENSIVE CARE UNIT IN AN ACUTE PSYCIATHRIC WARD 308.Mathias Toft: GENETIC STUDIES OF LRRK2 AND PINK1 IN PARKINSON'S DISEASE 309.Ingrid Løvold Mostad: IMPACT OF DIETARY FAT QUANTITY AND QUALITY IN TYPE 2 DIABETES WITH EMPHASIS ON MARINE N-3 FATTY ACIDS 310.Torill Eidhammer Sjøbakk: MR DETERMINED BRAIN METABOLIC PATTERN IN PATIENTS WITH BRAIN METASTASES AND ADOLESCENTS WITH LOW BIRTH WEIGHT 311.Vidar Beisvåg: PHYSIOLOGICAL GENOMICS OF HEART FAILURE: FROM TECHNOLOGY TO PHYSIOLOGY 312.Olav Magnus Søndenå Fredheim: HEALTH RELATED QUALITY OF LIFE ASSESSMENT AND ASPECTS OF THE CLINICAL PHARMACOLOGY OF METHADONE IN PATIENTS WITH CHRONIC NON-MALIGNANT PAIN 313.Anne Brantberg: FETAL AND PERINATAL IMPLICATIONS OF ANOMALIES IN THE GASTROINTESTINAL TRACT AND THE ABDOMINAL WALL 314.Erik Solligård: GUT LUMINAL MICRODIALYSIS 315.Elin Tollefsen: RESPIRATORY SYMPTOMS IN A COMPREHENSIVE POPULATION BASED STUDY AMONG ADOLESCENTS 13-19 YEARS. YOUNG-HUNT 1995-97 AND 2000-01; THE NORD-TRØNDELAG HEALTH STUDIES (HUNT) 316.Anne-Tove Brenne: GROWTH REGULATION OF MYELOMA CELLS 317.Heidi Knobel: FATIGUE IN CANCER TREATMENT – ASSESSMENT, COURSE AND 318. Torbjørn Dahl: CAROTID ARTERY STENOSIS. DIAGNOSTIC AND THERAPEUTIC 319.Inge-Andre Rasmussen jr.: FUNCTIONAL AND DIFFUSION TENSOR MAGNETIC RESONANCE IMAGING IN NEUROSURGICAL PATIENTS 320.Grete Helen Bratberg: PUBERTAL TIMING – ANTECEDENT TO RISK OR RESILIENCE ? EPIDEMIOLOGICAL STUDIES ON GROWTH, MATURATION AND HEALTH RISK BEHAVIOURS; THE YOUNG HUNT STUDY, NORD-TRØNDELAG, NORWAY 321.Sveinung Sørhaug: THE PULMONARY NEUROENDOCRINE SYSTEM. PHYSIOLOGICAL, PATHOLOGICAL AND TUMOURIGENIC ASPECTS 322.Olav Sande Eftedal: ULTRASONIC DETECTION OF DECOMPRESSION INDUCED VASCULAR MICROBUBBLES 323.Rune Bang Leistad: PAIN, AUTONOMIC ACTIVATION AND MUSCULAR ACTIVITY RELATED TO EXPERIMENTALLY-INDUCED COGNITIVE STRESS IN HEADACHE PATIENTS 324.Svein Brekke: TECHNIQUES FOR ENHANCEMENT OF TEMPORAL RESOLUTION IN THREE-DIMENSIONAL ECHOCARDIOGRAPHY 325. Kristian Bernhard Nilsen: AUTONOMIC ACTIVATION AND MUSCLE ACTIVITY IN RELATION TO MUSCULOSKELETAL PAIN 326.Anne Irene Hagen: HEREDITARY BREAST CANCER IN NORWAY. DETECTION AND PROGNOSIS OF BREAST CANCER IN FAMILIES WITH BRCA1GENE MUTATION 327.Ingebjørg S. Juel : INTESTINAL INJURY AND RECOVERY AFTER ISCHEMIA. AN EXPERIMENTAL STUDY ON RESTITUTION OF THE SURFACE EPITHELIUM, INTESTINAL PERMEABILITY, AND RELEASE OF BIOMARKERS FROM THE MUCOSA 328.Runa Heimstad: POST-TERM PREGNANCY 329.Jan Egil Afset: ROLE OF ENTEROPATHOGENIC ESCHERICHIA COLI IN CHILDHOOD DIARRHOEA IN NORWAY 330.Bent Håvard Hellum: IN VITRO INTERACTIONS BETWEEN MEDICINAL DRUGS AND HERBS ON CYTOCHROME P-450 METABOLISM AND P-GLYCOPROTEIN TRANSPORT 331.Morten André Høydal: CARDIAC DYSFUNCTION AND MAXIMAL OXYGEN UPTAKE MYOCARDIAL ADAPTATION TO ENDURANCE TRAINING 332. Andreas Møllerløkken: REDUCTION OF VASCULAR BUBBLES: METHODS TO PREVENT THE ADVERSE EFFECTS OF DECOMPRESSION 333.Anne Hege Aamodt: COMORBIDITY OF HEADACHE AND MIGRAINE IN THE NORD- TRØNDELAG HEALTH STUDY 1995-97 334. Brage Høyem Amundsen: MYOCARDIAL FUNCTION QUANTIFIED BY SPECKLE TRACKING AND TISSUE DOPPLER ECHOCARDIOGRAPHY – VALIDATION AND APPLICATION IN EXERCISE TESTING AND TRAINING 335.Inger Anne Næss: INCIDENCE, MORTALITY AND RISK FACTORS OF FIRST VENOUS THROMBOSIS IN A GENERAL POPULATION. RESULTS FROM THE SECOND NORD-TRØNDELAG HEALTH STUDY (HUNT2) 336.Vegard Bugten: EFFECTS OF POSTOPERATIVE MEASURES AFTER FUNCTIONAL ENDOSCOPIC SINUS SURGERY 337.Morten Bruvold: MANGANESE AND WATER IN CARDIAC MAGNETIC RESONANCE 338.Miroslav Fris: THE EFFECT OF SINGLE AND REPEATED ULTRAVIOLET RADIATION ON THE ANTERIOR SEGMENT OF THE RABBIT EYE 339.Svein Arne Aase: METHODS FOR IMPROVING QUALITY AND EFFICIENCY IN QUANTITATIVE ECHOCARDIOGRAPHY – ASPECTS OF USING HIGH FRAME RATE 340.Roger Almvik: ASSESSING THE RISK OF VIOLENCE: DEVELOPMENT AND VALIDATION OF THE BRØSET VIOLENCE CHECKLIST 341.Ottar Sundheim: STRUCTURE-FUNCTION ANALYSIS OF HUMAN ENZYMES INITIATING NUCLEOBASE REPAIR IN DNA AND RNA 342.Anne Mari Undheim: SHORT AND LONG-TERM OUTCOME OF EMOTIONAL AND BEHAVIOURAL PROBLEMS IN YOUNG ADOLESCENTS WITH AND WITHOUT READING DIFFICULTIES 343.Helge Garåsen: THE TRONDHEIM MODEL. IMPROVING THE PROFESSIONAL COMMUNICATION BETWEEN THE VARIOUS LEVELS OF HEALTH CARE SERVICES AND IMPLEMENTATION OF INTERMEDIATE CARE AT A COMMUNITY HOSPITAL COULD PROVIDE BETTER CARE FOR OLDER PATIENTS. SHORT AND LONG TERM EFFECTS 344.Olav A. Foss: "THE ROTATION RATIOS METHOD". A METHOD TO DESCRIBE ALTERED SPATIAL ORIENTATION IN SEQUENTIAL RADIOGRAPHS FROM ONE PELVIS 345.Bjørn Olav Åsvold: THYROID FUNCTION AND CARDIOVASCULAR HEALTH 346.Torun Margareta Melø: NEURONAL GLIAL INTERACTIONS IN EPILEPSY 347.Irina Poliakova Eide: FETAL GROWTH RESTRICTION AND PRE-ECLAMPSIA: SOME CHARACTERISTICS OF FETO-MATERNAL INTERACTIONS IN DECIDUA BASALIS 348.Torunn Askim: RECOVERY AFTER STROKE. ASSESSMENT AND TREATMENT; WITH FOCUS ON MOTOR FUNCTION 349.Ann Elisabeth Åsberg: NEUTROPHIL ACTIVATION IN A ROLLER PUMP MODEL OF CARDIOPULMONARY BYPASS. INFLUENCE ON BIOMATERIAL, PLATELETS AND COMPLEMENT 350.Lars Hagen: REGULATION OF DNA BASE EXCISION REPAIR BY PROTEIN INTERACTIONS AND POST TRANSLATIONAL MODIFICATIONS 351.Sigrun Beate Kjøtrød: POLYCYSTIC OVARY SYNDROME – METFORMIN TREATMENT IN ASSISTED REPRODUCTION 352.Steven Keita Nishiyama: PERSPECTIVES ON LIMB-VASCULAR HETEROGENEITY: IMPLICATIONS FOR HUMAN AGING, SEX, AND EXERCISE 353.Sven Peter Näsholm: ULTRASOUND BEAMS FOR ENHANCED IMAGE QUALITY 354.Jon Ståle Ritland: PRIMARY OPEN-ANGLE GLAUCOMA & EXFOLIATIVE GLAUCOMA. SURVIVAL, COMORBIDITY AND GENETICS 355.Sigrid Botne Sando: ALZHEIMER'S DISEASE IN CENTRAL NORWAY. GENETIC AND EDUCATIONAL ASPECTS 356.Parvinder Kaur: CELLULAR AND MOLECULAR MECHANISMS BEHIND METHYLMERCURY-INDUCED NEUROTOXICITY 357.Ismail Cüneyt Güzey: DOPAMINE AND SEROTONIN RECEPTOR AND TRANSPORTER GENE POLYMORPHISMS AND EXTRAPYRAMIDAL SYMPTOMS. STUDIES IN PARKINSON'S DISEASE AND IN PATIENTS TREATED WITH ANTIPSYCHOTIC OR ANTIDEPRESSANT DRUGS 358.Brit Dybdahl: EXTRA-CELLULAR INDUCIBLE HEAT-SHOCK PROTEIN 70 (Hsp70) – A ROLE IN THE INFLAMMATORY RESPONSE ? 359.Kristoffer Haugarvoll: IDENTIFYING GENETIC CAUSES OF PARKINSON'S DISEASE IN 360.Nadra Nilsen: TOLL-LIKE RECEPTOR 2 –EXPRESSION, REGULATION AND SIGNALING 361.Johan Håkon Bjørngaard: PATIENT SATISFACTION WITH OUTPATIENT MENTAL HEALTH SERVICES – THE INFLUENCE OF ORGANIZATIONAL FACTORS. 362.Kjetil Høydal : EFFECTS OF HIGH INTENSITY AEROBIC TRAINING IN HEALTHY SUBJECTS AND CORONARY ARTERY DISEASE PATIENTS; THE IMPORTANCE OF INTENSITY,, DURATION AND FREQUENCY OF TRAINING. 363.Trine Karlsen: TRAINING IS MEDICINE: ENDURANCE AND STRENGTH TRAINING IN CORONARY ARTERY DISEASE AND HEALTH. 364.Marte Thuen: MANGANASE-ENHANCED AND DIFFUSION TENSOR MR IMAGING OF THE NORMAL, INJURED AND REGENERATING RAT VISUAL PATHWAY 365.Cathrine Broberg Vågbø: DIRECT REPAIR OF ALKYLATION DAMAGE IN DNA AND RNA BY 2-OXOGLUTARATE- AND IRON-DEPENDENT DIOXYGENASES 366.Arnt Erik Tjønna: AEROBIC EXERCISE AND CARDIOVASCULAR RISK FACTORS IN OVERWEIGHT AND OBESE ADOLESCENTS AND ADULTS 367.Marianne W. Furnes: FEEDING BEHAVIOR AND BODY WEIGHT DEVELOPMENT: LESSONS FROM RATS 368.Lene N. Johannessen: FUNGAL PRODUCTS AND INFLAMMATORY RESPONSES IN HUMAN MONOCYTES AND EPITHELIAL CELLS 369.Anja Bye: GENE EXPRESSION PROFILING OF INHERITED AND ACQUIRED MAXIMAL OXYGEN UPTAKE – RELATIONS TO THE METABOLIC SYNDROME. 370.Oluf Dimitri Røe: MALIGNANT MESOTHELIOMA: VIRUS, BIOMARKERS AND GENES. A TRANSLATIONAL APPROACH 371.Ane Cecilie Dale: DIABETES MELLITUS AND FATAL ISCHEMIC HEART DISEASE. ANALYSES FROM THE HUNT1 AND 2 STUDIES 372.Jacob Christian Hølen: PAIN ASSESSMENT IN PALLIATIVE CARE: VALIDATION OF METHODS FOR SELF-REPORT AND BEHAVIOURAL ASSESSMENT 373.Erming Tian: THE GENETIC IMPACTS IN THE ONCOGENESIS OF MULTIPLE 374.Ole Bosnes: KLINISK UTPRØVING AV NORSKE VERSJONER AV NOEN SENTRALE TESTER PÅ KOGNITIV FUNKSJON 375.Ola M. Rygh: 3D ULTRASOUND BASED NEURONAVIGATION IN NEUROSURGERY. A CLINICAL EVALUATION 376.Astrid Kamilla Stunes: ADIPOKINES, PEROXISOME PROFILERATOR ACTIVATED RECEPTOR (PPAR) AGONISTS AND SEROTONIN. COMMON REGULATORS OF BONE AND FAT METABOLISM 377.Silje Engdal: HERBAL REMEDIES USED BY NORWEGIAN CANCER PATIENTS AND THEIR ROLE IN HERB-DRUG INTERACTIONS 378.Kristin Offerdal: IMPROVED ULTRASOUND IMAGING OF THE FETUS AND ITS CONSEQUENCES FOR SEVERE AND LESS SEVERE ANOMALIES 379.Øivind Rognmo: HIGH-INTENSITY AEROBIC EXERCISE AND CARDIOVASCULAR 380. Jo-Åsmund Lund: RADIOTHERAPY IN ANAL CARCINOMA AND PROSTATE CANCER 2009 381.Tore Grüner Bjåstad: HIGH FRAME RATE ULTRASOUND IMAGING USING PARALLEL 382.Erik Søndenaa: INTELLECTUAL DISABILITIES IN THE CRIMINAL JUSTICE SYSTEM 383.Berit Rostad: SOCIAL INEQUALITIES IN WOMEN'S HEALTH, HUNT 1984-86 AND 1995-97, THE NORD-TRØNDELAG HEALTH STUDY (HUNT) 384.Jonas Crosby: ULTRASOUND-BASED QUANTIFICATION OF MYOCARDIAL DEFORMATION AND ROTATION 385.Erling Tronvik: MIGRAINE, BLOOD PRESSURE AND THE RENIN-ANGIOTENSIN 386.Tom Christensen: BRINGING THE GP TO THE FOREFRONT OF EPR DEVELOPMENT 387.Håkon Bergseng: ASPECTS OF GROUP B STREPTOCOCCUS (GBS) DISEASE IN THE NEWBORN. EPIDEMIOLOGY, CHARACTERISATION OF INVASIVE STRAINS AND EVALUATION OF INTRAPARTUM SCREENING 388.Ronny Myhre: GENETIC STUDIES OF CANDIDATE TENE3S IN PARKINSON'S 389.Torbjørn Moe Eggebø: ULTRASOUND AND LABOUR 390.Eivind Wang: TRAINING IS MEDICINE FOR PATIENTS WITH PERIPHERAL ARTERIAL 391.Thea Kristin Våtsveen: GENETIC ABERRATIONS IN MYELOMA CELLS 392.Thomas Jozefiak: QUALITY OF LIFE AND MENTAL HEALTH IN CHILDREN AND ADOLESCENTS: CHILD AND PARENT PERSPECTIVES 393.Jens Erik Slagsvold: N-3 POLYUNSATURATED FATTY ACIDS IN HEALTH AND DISEASE – CLINICAL AND MOLECULAR ASPECTS 394.Kristine Misund: A STUDY OF THE TRANSCRIPTIONAL REPRESSOR ICER. REGULATORY NETWORKS IN GASTRIN-INDUCED GENE EXPRESSION 395.Franco M. Impellizzeri: HIGH-INTENSITY TRAINING IN FOOTBALL PLAYERS. EFFECTS ON PHYSICAL AND TECHNICAL PERFORMANCE 396.Kari Hanne Gjeilo: HEALTH-RELATED QUALITY OF LIFE AND CHRONIC PAIN IN PATIENTS UNDERGOING CARDIAC SURGERY 397.Øyvind Hauso: NEUROENDOCRINE ASPECTS OF PHYSIOLOGY AND DISEASE 398.Ingvild Bjellmo Johnsen: INTRACELLULAR SIGNALING MECHANISMS IN THE INNATE IMMUNE RESPONSE TO VIRAL INFECTIONS 399.Linda Tømmerdal Roten: GENETIC PREDISPOSITION FOR DEVELOPMENT OF PREEMCLAMPSIA – CANDIDATE GENE STUDIES IN THE HUNT (NORD-TRØNDELAG HEALTH STUDY) POPULATION 400.Trude Teoline Nausthaug Rakvåg: PHARMACOGENETICS OF MORPHINE IN CANCER 401.Hanne Lehn: MEMORY FUNCTIONS OF THE HUMAN MEDIAL TEMPORAL LOBE STUDIED WITH fMRI 402.Randi Utne Holt: ADHESION AND MIGRATION OF MYELOMA CELLS – IN VITRO 403.Trygve Solstad: NEURAL REPRESENTATIONS OF EUCLIDEAN SPACE 404.Unn-Merete Fagerli: MULTIPLE MYELOMA CELLS AND CYTOKINES FROM THE BONE MARROW ENVIRONMENT; ASPECTS OF GROWTH REGULATION AND MIGRATION 405.Sigrid Bjørnelv: EATING– AND WEIGHT PROBLEMS IN ADOLESCENTS, THE YOUNG 406.Mari Hoff: CORTICAL HAND BONE LOSS IN RHEUMATOID ARTHRITIS. EVALUATING DIGITAL X-RAY RADIOGRAMMETRY AS OUTCOME MEASURE OF DISEASE ACTIVITY, RESPONSE VARIABLE TO TREATMENT AND PREDICTOR OF BONE DAMAGE 407.Siri Bjørgen: AEROBIC HIGH INTENSITY INTERVAL TRAINING IS AN EFFECTIVE TREATMENT FOR PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE 408.Susanne Lindqvist: VISION AND BRAIN IN ADOLESCENTS WITH LOW BIRTH WEIGHT 409.Torbjørn Hergum: 3D ULTRASOUND FOR QUANTITATIVE ECHOCARDIOGRAPHY 410.Jørgen Urnes: PATIENT EDUCATION IN GASTRO-OESOPHAGEAL REFLUX DISEASE. VALIDATION OF A DIGESTIVE SYMPTOMS AND IMPACT QUESTIONNAIRE AND A RANDOMISED CONTROLLED TRIAL OF PATIENT EDUCATION 411.Elvar Eyjolfsson: 13C NMRS OF ANIMAL MODELS OF SCHIZOPHRENIA 412.Marius Steiro Fimland: CHRONIC AND ACUTE NEURAL ADAPTATIONS TO STRENGTH 413.Øyvind Støren: RUNNING AND CYCLING ECONOMY IN ATHLETES; DETERMINING FACTORS, TRAINING INTERVENTIONS AND TESTING 414.Håkon Hov: HEPATOCYTE GROWTH FACTOR AND ITS RECEPTOR C-MET. AUTOCRINE GROWTH AND SIGNALING IN MULTIPLE MYELOMA CELLS 415.Maria Radtke: ROLE OF AUTOIMMUNITY AND OVERSTIMULATION FOR BETA-CELL DEFICIENCY. EPIDEMIOLOGICAL AND THERAPEUTIC PERSPECTIVES 416.Liv Bente Romundstad: ASSISTED FERTILIZATION IN NORWAY: SAFETY OF THE REPRODUCTIVE TECHNOLOGY 417.Erik Magnus Berntsen: PREOPERATIV PLANNING AND FUNCTIONAL NEURONAVIGATION – WITH FUNCTIONAL MRI AND DIFFUSION TENSOR TRACTOGRAPHY IN PATIENTS WITH BRAIN LESIONS 418.Tonje Strømmen Steigedal: MOLECULAR MECHANISMS OF THE PROLIFERATIVE RESPONSE TO THE HORMONE GASTRIN 419.Vidar Rao: EXTRACORPOREAL PHOTOCHEMOTHERAPY IN PATIENTS WITH CUTANEOUS T CELL LYMPHOMA OR GRAFT-vs-HOST DISEASE 420.Torkild Visnes: DNA EXCISION REPAIR OF URACIL AND 5-FLUOROURACIL IN HUMAN CANCER CELL LINES 2010 421.John Munkhaugen: BLOOD PRESSURE, BODY WEIGHT, AND KIDNEY FUNCTION IN THE NEAR-NORMAL RANGE: NORMALITY, RISK FACTOR OR MORBIDITY ? 422.Ingrid Castberg: PHARMACOKINETICS, DRUG INTERACTIONS AND ADHERENCE TO TREATMENT WITH ANTIPSYCHOTICS: STUDIES IN A NATURALISTIC SETTING 423.Jian Xu: BLOOD-OXYGEN-LEVEL-DEPENDENT-FUNCTIONAL MAGNETIC RESONANCE IMAGING AND DIFFUSION TENSOR IMAGING IN TRAUMATIC BRAIN INJURY RESEARCH 424.Sigmund Simonsen: ACCEPTABLE RISK AND THE REQUIREMENT OF PROPORTIONALITY IN EUROPEAN BIOMEDICAL RESEARCH LAW. WHAT DOES THE REQUIREMENT THAT BIOMEDICAL RESEARCH SHALL NOT INVOLVE RISKS AND BURDENS DISPROPORTIONATE TO ITS POTENTIAL BENEFITS MEAN? 425.Astrid Woodhouse: MOTOR CONTROL IN WHIPLASH AND CHRONIC NON- TRAUMATIC NECK PAIN 426.Line Rørstad Jensen: EVALUATION OF TREATMENT EFFECTS IN CANCER BY MR IMAGING AND SPECTROSCOPY 427.Trine Moholdt: AEROBIC EXERCISE IN CORONARY HEART DISEASE 428.Øystein Olsen: ANALYSIS OF MANGANESE ENHANCED MRI OF THE NORMAL AND INJURED RAT CENTRAL NERVOUS SYSTEM 429.Bjørn H. Grønberg: PEMETREXED IN THE TREATMENT OF ADVANCED LUNG 430.Vigdis Schnell Husby: REHABILITATION OF PATIENTS UNDERGOING TOTAL HIP ARTHROPLASTY WITH FOCUS ON MUSCLE STRENGTH, WALKING AND AEROBIC ENDURANCE PERFORMANCE 431.Torbjørn Øien: CHALLENGES IN PRIMARY PREVENTION OF ALLERGY. THE PREVENTION OF ALLERGY AMONG CHILDREN IN TRONDHEIM (PACT) STUDY. 432.Kari Anne Indredavik Evensen: BORN TOO SOON OR TOO SMALL: MOTOR PROBLEMS 433.Lars Adde: PREDICTION OF CEREBRAL PALSY IN YOUNG INFANTS. COMPUTER BASED ASSESSMENT OF GENERAL MOVEMENTS 434.Magnus Fasting: PRE- AND POSTNATAL RISK FACTORS FOR CHILDHOOD 435.Vivi Talstad Monsen: MECHANISMS OF ALKYLATION DAMAGE REPAIR BY HUMAN 436.Toril Skandsen: MODERATE AND SEVERE TRAUMATIC BRAIN INJURY. MAGNETIC RESONANCE IMAGING FINDINGS, COGNITION AND RISK FACTORS FOR DISABILITY 437.Ingeborg Smidesang: ALLERGY RELATED DISORDERS AMONG 2-YEAR OLDS AND ADOLESCENTS IN MID-NORWAY – PREVALENCE, SEVERITY AND IMPACT. THE PACT STUDY 2005, THE YOUNG HUNT STUDY 1995-97 438.Vidar Halsteinli: MEASURING EFFICIENCY IN MENTAL HEALTH SERVICE DELIVERY: A STUDY OF OUTPATIENT UNITS IN NORWAY 439.Karen Lehrmann Ægidius: THE PREVALENCE OF HEADACHE AND MIGRAINE IN RELATION TO SEX HORMONE STATUS IN WOMEN. THE HUNT 2 STUDY 440.Madelene Ericsson: EXERCISE TRAINING IN GENETIC MODELS OF HEART FAILURE 441.Marianne Klokk: THE ASSOCIATION BETWEEN SELF-REPORTED ECZEMA AND COMMON MENTAL DISORDERS IN THE GENERAL POPULATION. THE HORDALAND HEALTH STUDY (HUSK) 442.Tomas Ottemo Stølen: IMPAIRED CALCIUM HANDLING IN ANIMAL AND HUMAN CARDIOMYOCYTES REDUCE CONTRACTILITY AND INCREASE ARRHYTHMIA POTENTIAL – EFFECTS OF AEROBIC EXERCISE TRAINING 443.Bjarne Hansen: ENHANCING TREATMENT OUTCOME IN COGNITIVE BEHAVIOURAL THERAPY FOR OBSESSIVE COMPULSIVE DISORDER: THE IMPORTANCE OF COGNITIVE FACTORS 444.Mona Løvlien: WHEN EVERY MINUTE COUNTS. FROM SYMPTOMS TO ADMISSION FOR ACUTE MYOCARDIAL INFARCTION WITH SPECIAL EMPHASIS ON GENDER DIFFERECES 445.Karin Margaretha Gilljam: DNA REPAIR PROTEIN COMPLEXES, FUNCTIONALITY AND SIGNIFICANCE FOR REPAIR EFFICIENCY AND CELL SURVIVAL 446.Anne Byriel Walls: NEURONAL GLIAL INTERACTIONS IN CEREBRAL ENERGY – AND AMINO ACID HOMEOSTASIS – IMPLICATIONS OF GLUTAMATE AND GABA 447.Cathrine Fallang Knetter: MECHANISMS OF TOLL-LIKE RECEPTOR 9 ACTIVATION 448.Marit Følsvik Svindseth: A STUDY OF HUMILIATION, NARCISSISM AND TREATMENT OUTCOME IN PATIENTS ADMITTED TO PSYCHIATRIC EMERGENCY UNITS 449.Karin Elvenes Bakkelund: GASTRIC NEUROENDOCRINE CELLS – ROLE IN GASTRIC NEOPLASIA IN MAN AND RODENTS 450.Kirsten Brun Kjelstrup: DORSOVENTRAL DIFFERENCES IN THE SPATIAL REPRESENTATION AREAS OF THE RAT BRAIN 451.Roar Johansen: MR EVALUATION OF BREAST CANCER PATIENTS WITH POOR 452.Rigmor Myran: POST TRAUMATIC NECK PAIN. EPIDEMIOLOGICAL, NEURORADIOLOGICAL AND CLINICAL ASPECTS 453.Krisztina Kunszt Johansen: GENEALOGICAL, CLINICAL AND BIOCHEMICAL STUDIES IN LRRK2 – ASSOCIATED PARKINSON'S DISEASE 454.Pål Gjerden: THE USE OF ANTICHOLINERGIC ANTIPARKINSON AGENTS IN NORWAY. EPIDEMIOLOGY, TOXICOLOGY AND CLINICAL IMPLICATIONS

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10 promising.indd

Table of Contents Strategies for Addressing The DWI Offender: 10 PROMISING SENTENCING PRACTICES A compendium of promising sentencing practices proposed at theNHTSA National DWI Sentencing Summit at The National Judicial CollegeMarch 15-16, 2004 Strategies for Addressing The DWI Offender: A compendium of promising sentencing practices proposed at the NHTSA National

Mcneil, a johnson & johnson subsidiary fda case study

McNeil, a Johnson & Johnson Subsidiary FDA Case StudyWarren AdisHagan School of Business, Iona College, wadis@iona.edu Follow this and additional works at: Recommended CitationAdis, Warren (2014) "McNeil, a Johnson & Johnson Subsidiary FDA Case Study," Communications of the IIMA: Vol. 14: Iss. 3, Article2.Available at: This Article is brought to you for free and open access by CSUSB ScholarWorks. It has been accepted for inclusion in Communications of the IIMA byan authorized administrator of CSUSB ScholarWorks. For more information, please contact .