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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
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
Dr. philos., NTNU, Det medisinske fakultet, Institutt for laboratoriemedisin, barne- og
kvinnesykdommer, 251110. Veiledere: Lars Slørdal og Jørgen G. Bramness.
Table of contents
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
5. Materials and methods
5.4 Statistics 20
7.1. Methodology 32
7.2. Main results 33
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.
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
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
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
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).
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
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
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.
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
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.
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
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
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.
1. Nemeroff CB, Putnam JS. Anticholinergics and Amantadine. In:
Kaplan & Sadock's Comprehensive Textbook of Psychiatry, eds
Sadock JB, Sadock VA. Philadelphia: Lippincott Williams &
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2. WHO Collaborating Centre for Drug Statistics Methodology.
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new compound (B.S.5930). Br Med J 1955; Aug. 6: 352-355
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orphenadrine (Disipal) hydrochloride. Results in 176 cases.
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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 &
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Sadock VA. Philadelphia: Lippincott Williams & Wilkins, 2005;
18. Pittler MH, White AR. Efficacy and effectiveness. Focus Alternat
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19. Fleischhacker WW, Goodwin GM. Effectiveness as an outcome
measure for treatment trials in psychiatry. World Psychiatry 2009;
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for symptomatic management of Parkinson's disease. Cochrane
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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:
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KP, Murray RM, Markwick A, Lewis SW. Randomized
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26. Strom BL. What is pharmacoepidemiology? In:
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27. Sangster B. Orphenadrine intoxication. Geneesmiddelen Bull
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):
: "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.]
: "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.]
: "…, 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]
: "the group using chlorprotixene" [the chlorprotixene using
"…, use of anticholinergics and use of specific antipsychotics " […, if the patient used anticholinergics and the use of specific antipsychotics]
: "prior to" [preceeding]
A few misspellings have been corrected.
Dissertations at the Faculty of Medicine, NTNU
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
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
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
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
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
74. Martin Svartberg: AN INVESTIGATION OF PROCESS AND OUTCOME OF SHORT-TERM
75. Stig Arild Slørdahl: AORTIC REGURGITATION. 76. Harold C Sexton: STUDIES RELATING TO THE TREATMENT OF SYMPTOMATIC NON-
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
93. Sverre Helge Torp: erb
B 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
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
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
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
: 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
147.Heidi Brurok: MANGANESE AND THE HEART. A Magic Metal with Diagnostic and
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
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-
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
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
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
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
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
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307.Arne Vaaler: EFFECTS OF PSYCHIATRIC INTENSIVE CARE UNIT IN AN ACUTE
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310.Torill Eidhammer Sjøbakk: MR DETERMINED BRAIN METABOLIC PATTERN IN
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311.Vidar Beisvåg: PHYSIOLOGICAL GENOMICS OF HEART FAILURE: FROM
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312.Olav Magnus Søndenå Fredheim: HEALTH RELATED QUALITY OF LIFE ASSESSMENT
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313.Anne Brantberg: FETAL AND PERINATAL IMPLICATIONS OF ANOMALIES IN THE
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314.Erik Solligård: GUT LUMINAL MICRODIALYSIS 315.Elin Tollefsen: RESPIRATORY SYMPTOMS IN A COMPREHENSIVE POPULATION
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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
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320.Grete Helen Bratberg: PUBERTAL TIMING – ANTECEDENT TO RISK OR RESILIENCE ?
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321.Sveinung Sørhaug: THE PULMONARY NEUROENDOCRINE SYSTEM.
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322.Olav Sande Eftedal: ULTRASONIC DETECTION OF DECOMPRESSION INDUCED
323.Rune Bang Leistad: PAIN, AUTONOMIC ACTIVATION AND MUSCULAR ACTIVITY
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324.Svein Brekke: TECHNIQUES FOR ENHANCEMENT OF TEMPORAL RESOLUTION IN
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333.Anne Hege Aamodt: COMORBIDITY OF HEADACHE AND MIGRAINE IN THE NORD-
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334. Brage Høyem Amundsen: MYOCARDIAL FUNCTION QUANTIFIED BY SPECKLE
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336.Vegard Bugten: EFFECTS OF POSTOPERATIVE MEASURES AFTER FUNCTIONAL
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338.Miroslav Fris: THE EFFECT OF SINGLE AND REPEATED ULTRAVIOLET RADIATION
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416.Liv Bente Romundstad: ASSISTED FERTILIZATION IN NORWAY: SAFETY OF THE
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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 StudyWarren AdisHagan School of Business, Iona College, firstname.lastname@example.org 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 .