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The purpose of the study was to investigate the clinical effect of a clinical pharmacist (CP) intervention upon admission to hospital on inpatient harm and to assess a potential educational bias. Over 16 months, 593 adult patients taking ≥4 medications daily were included from three Danish acute medicine wards. Patients were randomized to either the CP intervention or the usual care (prospective control). To assess a potential educational bias, a retrospective control group was formed by randomization. The CP intervention comprised medication history, medication reconciliation, medication review and entry of proposed prescriptions into the electronic prescribing system. The primary outcome of inpatient harm was identified using triggers from the Institute of Healthcare Improvement Global Trigger Tool. Harms were validated and rated for severity by two independent and blinded outcome panels. Secondary end-points were harms per patient, length of hospital stay, readmissions and 1-year mortality. Harm affected 11% of the patients in the intervention group compared to 17% in the combined control group, odds ratio (OR) 0.57 (CI 0.32-1.02, p = 0.06). The incidence of harm was similar in the intervention and prospective control groups, OR 0.80 (CI 0.40-1.59, p = 0.52) but occurred less frequently in the intervention than in the retrospective control group OR 0.46 (CI 0.25-0.85, p = 0.01). An educational bias from the intervention to the control group might have contributed to this negative outcome. In conclusion, the CP intervention at admission to hospital had no statistically significant effect on inpatient harm.

European freshwater habitats have experienced a severe loss of plant diversity, regionally and locally, over the last century or more. One important and well-established driver of change is eutrophication, which has increased with rising population density and agricultural intensification. However, reduced disturbance of lake margins may have played an additional key role. The geographical variation in water chemistry, which has set the scene for - and interacted with - anthropogenic impact, is much less well understood. We took advantage of some recently completed regional plant distribution surveys, relying on hundreds of skilled citizen scientists, and analyzed the hydrophyte richness to environment relations in five contiguous South-Scandinavian regions. For three of the regions, we also assessed changes to the freshwater flora over the latest 50-80 years. We found a considerable variation in background total phosphorus concentrations and alkalinity, both within and between regions. The prevalence of functional groups differed between regions in accordance with the environmental conditions and the species' tolerance to turbid waters. Similarly, the historical changes within regions followed the same trend in correspondence to the altered environmental conditions over time. Small submerged species decreased relative to tall submerged and floating-leaved species along the regional and historical eutrophication gradients. These changes were accompanied by systematically greater relative abundance of species of higher phosphorus prevalence. We conclude that species traits in close correspondence with anthropogenic impacts are the main determinants of local, regional and historical changes of species distribution and occupancy, while pure biogeography plays a minor role. Conservation measures, such as re-oligotrophication and re-established disturbance regimes through grazing and water level fluctuations, may help reduce the tall reed vegetation, restore the former richness of the freshwater flora and safeguard red-listed species, although extended time delays are anticipated in nutrient-rich regions, in which species only survive at minute abundance in isolated refugia.

The use of fixed-dose combinations (FDCs) in the daily practice of pharmacotherapy is increasing after years in the shadows. The main reasons for this renewed popularity are the increasing number of drugs prescribed per patient and the complexity of current pharmacotherapy. A lack of efficacy of current monotherapies in many diseases together with advances in knowledge on pathophysiological disease mechanisms have also created a push towards development of new FDCs. For the regulatory authorities in Europe, however, it is unclear whether FDCs in general have a positive benefit–risk balance. Hence, more research is needed to show that use of FDCs improves treatment effectiveness through better compliance, adherence and quality of life for patients, which may lead to a positive pharmacoeconomical benefit for society. Evidence-based data are thus needed, especially for those patient groups requiring multiple drugs—for example, the elderly. In this context, hospital practice regarding FDCs is crucial, as the recommended pharmacotherapy at discharge of the patient serves as a role model for outpatient care, and therefore needs greater recognition. The benefit–risk balance and pharmacoeconomical consequences of FDCs should also be a subject for attention in the hospital pharmacy setting.

Objectives To highlight the health-related quality of life scale scores for Saudi patients with different types of cancer, to get understanding and foundation for improvements. To suggest suitable plans for quality of life improvement based on study outcome. The role of oncology pharmacy will be stressed. Methods A cross-sectional descriptive study was conducted at a tertiary regional hospital using the European Organization for Research and Treatment of Cancer QLQ-C30 questionnaire. Attendees were patients diagnosed with any type of cancer and eligible for active anticancer treatment and/or palliative care. Results Quality of life was evaluated for 87 participants. Most of patients were aged between 51 and 60 years; and 50% had active treatment with chemotherapy. Patients seemed to perform well with respect to average scores in both the symptoms and the functional health status scales. The mean score for the global quality of life scale was 47.2 ± 27.1, while the range of mean scores for the five function subscales was 59.0 ± 27.1 to 81.6 ± 13.8, indicating average level of general wellbeing with above average to high level of functional health status, while >50% of the patients met the operational criterion having less severe symptoms. Outpatients generally had somewhat higher scores as compared to hospitalized patients. Conclusion The general quality of life seemed satisfactory, but there is still need to improve care. Based on results from other studies, oncology pharmacists’ roles are essential to improve quality of life through treatment counseling, follow-up on drug support therapy, stress on patient’s education through specific programs, review and update the local guidelines, and conduct more research.

Background The majority of hospitalised patients have drug-related problems. Clinical pharmacist services including medication history, medication reconciliation and medication review may reduce the number of drug-related problems. Acute and emergency hospital services have changed considerably during the past decade in Denmark, and the new fast-paced workflows pose new challenges for the provision of clinical pharmacist service. Objective To describe and evaluate a method for a clinical pharmacist service that is relevant and fit the workflow of the medical care in the acute ward. Setting Acute wards at three Danish hospitals. Methods The clinical pharmacist intervention comprised medication history, medication reconciliation, medication review, medical record entries and entry of prescription templates into the electronic medication module. Drug-related problems were categorised using The PCNE Classification V6.2. Inter-rater agreement analysis was used to validate the tool. Acceptance rates were measured as the physicians’ approval of prescription templates and according to outcome in the PCNE classification. Main outcome measure Acceptance rate of the clinical pharmacists’ interventions through the described method and inter-rater agreement using the PCNE classification for drug-related problems. Results During 17 months, 188 patients were included in this study (average age 72 years and 55 % women). The clinical pharmacists found drug-related problems in 85 % of the patients. In the 1,724 prescriptions, 538 drug-related problems were identified. The overall acceptance rate by the physicians for the proposed interventions was 76 % (95 % CI 74–78 %). There was a substantial inter-rater agreement when using the PCNE classification system. Conclusion The methods for a clinical pharmacist service in the acute ward in this study have been demonstrated to be relevant and timely. The method received a high acceptance rate, regardless of no need for oral communication, and a substantial inter-rater agreement when classifying the drug-related problems.

Objectives Patients’ own drugs (PODs) are the medicines that patients have obtained in the community setting and bring to hospital. Little is known about the frequency with which patients bring PODs when admitted to hospital and the quality of these drugs has not been well investigated. The purpose of this study was to evaluate the quantity and quality of the PODs brought to hospital during admission. Methods Clinical pharmacists in four wards at three different hospitals evaluated the quantity and quality of PODs. The quantity of PODs relates to the number of patients who brought one or more of their medicines to hospital and the total number of PODs. The quality of PODs was evaluated by assessing the appearance, container, labelling, identification of contents, storage conditions and expiration, and thereby the usability of the POD. Results From March 2010 to July 2011, 4600 drugs from 529 patients were assessed. In total, 59% of patients took PODs to hospital and 43% (n=1985) of drugs from patients’ medication histories were brought to the hospital. The majority of PODs were usable (58.6%, n=1164) but most were unnecessary (52.3%, n=1039) because substitution was possible. In total, 92.5% (n=1836) of all PODs were not used during admission, although 33.5% (n=615) of these added information to the patients’ medication history. Conclusions More than half of patients brought PODs to hospital which gave the advantage of providing medication history. The majority of PODs were suitable for use in hospital. Only 7.5% of all PODs were actually used because substitution to generic or equivalent drugs from the hospital9s formulary was preferred.

Objective To investigate the uracil arabinoside/cytarabine (Ara-U/Ara-C) ratios with the lower dose in adult acute myeloid leukaemia (AML) induction therapy (100 mg/m 2 Ara-C) where no enzyme saturation is expected. Methods A precise and robust high-performance liquid chromatography (HPLC) method for simultaneous determination of Ara-C and its main inactive metabolite Ara-U in human plasma was developed and validated. Nineteen patients with acute myeloid leukaemia were treated with Ara-C in a dose of 100 mg/m 2 together with daunorubicin and etoposide. Plasma concentrations were used to construct the standard normality plot to indicate towards two different phenotypes for the deamination enzyme. This was confirmed with the Shapiro–Wilks test for normality and a histogram of the distribution of the ratios. Results The lower limits of quantification (LLoQ) of the developed method were 32 ng/ml and 10 ng/ml for Ara-C and Ara-U, respectively. Precision, accuracy, recovery, selectivity and stability varied by no more than 15% at concentrations above LLoQ and by 20% at LLoQ, except for long-term stability of Ara-U. Both the Shapiro–Wilks test for normality and the histogram showed a unimodal distribution. The non-transformed values of the Ara-U/Ara-C ratios were between 0.3 and 17.7 (median 2.2). No correlations between Ara-U/Ara-C ratios and age, sex, liver or renal function or treatment outcome were found. Fifteen of the 19 patients had complete remission of the disease and 2 had partial remission. Conclusions Division into slow and fast Ara-C metabolisers in this patient population could not be made and specific dose individualisations can therefore not be recommended.

It is disputed whether anxiety disorders, like social anxiety disorder, are characterized by serotonin over- or underactivity. Here, we evaluated whether our recent finding of elevated neural serotonin synthesis rate in patients with social anxiety disorder could be reproduced in a separate cohort, and whether allelic variation in the tryptophan hydroxylase-2 (TPH2) G-703T polymorphism relates to differences in serotonin synthesis assessed with positron emission tomography. Eighteen social anxiety disorder patients and six healthy controls were scanned during 60 minutes in a resting state using positron emission tomography and 5-hydroxy-L-[β -11C]tryptophan, [11C]5-HTP, a substrate of the second enzymatic step in serotonin synthesis. Parametric images were generated, using the reference Patlak method, and analysed using Statistical Parametric Mapping (SPM8). Blood samples for genotyping of the TPH2 G-703T polymorphism were obtained from 16 social anxiety disorder patients (T carriers: n=5, GG carriers: n=11). A significantly elevated [11C]5-HTP accumulation rate, indicative of enhanced decarboxylase activity and thereby serotonin synthesis capacity, was detected in social anxiety disorder patients compared with controls in the hippocampus and basal ganglia nuclei and, at a more lenient (uncorrected) statistical threshold, in the amygdala and anterior cingulate cortex. In patients, the serotonin synthesis rate in the amygdala and anterior cingulate cortex was significantly elevated in TPH2 T carriers in comparison with GG homozygotes. Our results support that social anxiety disorder entails an overactive presynaptic serotonergic system that, in turn, seems functionally influenced by the TPH2 G-703T polymorphism in emotionally relevant brain regions.

Interpatient variability in the pharmacokinetics (PK) of cytarabine, etoposide, and daunorubicin following body surface area-adjusted doses calls for studies that point to other covariates to explain this variability. The purpose of this study was to investigate such relationships and give insights into the PK of this combination treatment.A prospective population PK study of twenty-three patients with acute myeloid leukemia was undertaken. Plasma concentrations of patients were determined by high-pressure liquid chromatography. PK models were developed with NONMEM; for daunorubicin, PK information from a prior study was utilized.Baseline white blood cell count (bWBC) influenced the PK for all drugs. A small, statistically insignificant improvement in model fit was achieved when a relationship between bWBC and daunorubicin central volume of distribution was included. The volume increased 1.9% for each increase in bWBC by 1 × 10(6) cells/mL. The clearances of etoposide and cytarabine were significantly increased and decreased, respectively, by increased bWBC. Tenfold changes in bWBC were needed for these relationships to have potential clinical relevance. A decrease in creatinine clearance of 60 mL/min resulted in a decrease in etoposide clearance of 32%.Population-based models characterized the PK for all three drugs. bWBC was a significant covariate for etoposide and cytarabine and showed a trend for daunorubicin. Linking the significant bWBC relationships and the relationship between kidney function and etoposide clearance to clinical end points would support dose individualization. Patients with above-normal creatinine clearances and high bWBC may receive sub-optimal treatment due to elevated etoposide clearances.

Introduction The pathophysiologic and neurochemical characteristics of neuropathic pain must be considered in the search for new treatment targets. Breakthroughs in the understanding of the structural and biochemical changes in neuropathy have opened up possibilities to explore new treatment paradigms. However, long term sequels from the damage are still difficult to treat. Aim of the study To examine the validity of pharmacological treatments in humans and animals for neuropathic pain. Method An overview from the literature and own experiences of pharmacological treatments employed to interfere in pain behavior in different animal models was performed. Results The treatment principles tested in animal models of neuropathic pain may have predictive validity for treatment of human neuropathies. Opioids, neurotransmitter blockers, drugs interfering with the prostaglandin syntheses as well as voltage gated sodium channel blockers and calcium channel blockers are treatment principles having efficacy and similar potency in humans and in animals. Alternative targets have been identified and have shown promising results in the validated animal models. Modulators of the glutamate system with an increased expression of glutamate re-uptake transporters, inhibition of pain promoters as nitric oxide and prostaglandins need further exploration. Modulation of cytokines and neurotrophins in neuropathic pain implies new targets for study. Further, a combination of different analgesic treatments may as well improve management of neuropathic pain, changing the benefit/risk ratio. Implications Not surprisingly most pharmacologic principles that are tested in animal models of neuropathic pain are also found to be active in humans. Whereas many candidate drugs that were promising in animal models of neuropathic pain turned out not to be effective or too toxic in humans, animal models for neuropathic pain are still the best tools available to learn more about mechanisms of neuropathic pain. Better understanding of pathogenesis is the most hopeful approach to improve treatment of neuropathic pain.

Introduction Animal disease models are predictive for signs seen in disease. They may rarely mimic all signs in a specific disease in humans with respect to etiology, cause or development. Several models have been developed for different pain states and the alteration of behavior has been interpreted as a response to external stimulus or expression of pain or discomfort. Considerable attention must be paid not to interpret other effects such as somnolence or motor impairment as a pain response and similarly not to misinterpret the response of analgesics. Neuropathic pain is caused by injury or disease of the somatosensory system. The clinical manifestations of neuropathic pain vary including both stimulus-evoked and non-stimulus evoked (spontaneous) symptoms. By pharmacological intervention, the threshold for allodynia and hyperalgesia in the various pain modalities can be modulated and measured in animals and humans. Animal models have been found most valuable in studies on neuropathic pain and its treatment. Aim of the study With these interpretation problems in mind, the present text aims to describe the most frequently used animal models of neuropathic pain induced by mechanical nerve injury. Methods The technical surgical performance of these models is described as well as pain behavior based on the authors own experience and from a literature survey. Results Nerve injury in the hind limb of rats and mice is frequently used in neuropathic pain models and the different types of lesion may afford difference in the spread and quality of the pain provoked. The most frequently used models are presented, with special focus on the spared nerve injury (SNI) and the spinal nerve ligation/transection (SNL/SNT) models, which are extensively used and validated in rats and mice. Measures of mechanical and thermal hypersensitivity with von Frey filaments and Hargreaves test, respectively, are described and shown in figures. Conclusions A number of animal models have been developed and described for neuropathic pain showing predictive value in parallel for both humans and animals. On the other hand, there are still large knowledge gaps in the pathophysiologic mechanisms for the development, maintenance and progression of the neuropathic pain syndrome Implications Better understanding of pathogenic mechanisms of neuropathic pain in animal models may support the search for new treatment paradigms in patients with complex neuropathic pain conditions

Glutamate is the major excitatory amino acid in the mammalian CNS and is involved in transmission of pain together with processes for cognition, memory and learning. In order to terminate glutamatergic neurotransmission and avoid excitotoxic damage, a balanced glutamate homeostasis is of critical importance. The level of glutamate in the synaptic cleft is regulated through the action of five subtypes of excitatory amino acid transporters (EAAT1-5). Ceftriaxone, a β-lactam, induces EAAT-2 and has proven effect for the treatment of neuropathic pain. This pilot study investigated the effects of ceftriaxone upon acute and inflammatory pain and additionally, the analgesic effect of ceftriaxone after introduction of neuropathic pain. Methods Rats were tested before, during and after treatment of ceftriaxone for changes in response to both mechanical and thermal stimuli, using calibrated von Frey filaments and Hargreaves instrument, respectively. Inflammatory responses were investigated by assessing the response to intra-plantar injections of formalin; lastly, neuropathic pain was introduced using the spinal nerve ligation (SNL) model after which changes in both mechanical and thermal responses were again investigated. Results A significant increase in mechanical withdrawal threshold was observed following acute pain inducement in ceftriaxone treated rats. A marked increase in thermal withdrawal latency was also observed. In response to intra plantar administered formalin, ceftriaxone delayed the intensity of nocifensive behaviours. Applying the SNL model of neuropathic pain on naive rats created significant mechanical allodynia, but only a negligibly different response to thermal stimulation. After treatment with ceftriaxone the treated rats developed a hypoalgesic response to thermal stimulation, whilst the response to mechanical pain was insignificant. Conclusion In conclusion, ceftriaxone clearly interfered in the transmission of noxious signalling and proved in this study to have an effect upon acute thermal and mechanical pain thresholds as well as pathologic pain conditions. The present results are a piece in the large puzzle where administration route, dosage and pain models must be thoroughly investigated before a study can be planned for a proof of concept in different clinical pain states. Implications The current study demonstrates that ceftriaxone has a mitigating effect upon many pain modalities including acute and inflammatory, and that these modalities should be included in future studies characterising the anti-nociceptive effect of beta-lactams such as ceftriaxone. The fact that β-lactams also has antibiotic properties implies that similar chemical structures could be identified with the positive effect upon expression levels of EAAT2, but lacking the antibiotic side effect.

Purpose Post-marketing safety studies of adverse drug reactions (ADRs) form an important part of pharmacovigilance. Countries having a formal pharmacovigilance system to a large extent rely on voluntary ADR reporting from health professionals through spontaneous report systems. The contribution of pharmacists in ADR reporting, although varies significantly among countries. Pharmacists in community pharmacies are in a unique position for detection of experienced ADRs by the drug users. The study reports from a study on community pharmacy internship students' proactive role in ADR detection through direct encountering and questioning with drug users. Method Pharmacy students undertaking internship in a community pharmacy were approached. Thirteen students from nine community pharmacies participated in the project as data collectors. Prior to the study students attended an educational seminar focusing on ADR detection and reporting in general. Ibuprofen was chosen as the drug of study. Pharmacy students approached recurrent drug users purchasing the drug. Participating users were asked about experienced ADRs linked to ibuprofen use. Reported ADRs were collected and analysed. Results Hundred and twenty eight ibuprofen users participated in the study out of who thirty three reported forty five ADRs possibly linked to ibuprofen use. The reported ADRs followed earlier reported patterns of distribution with gastric pain showing up as the most commonly reported symptom followed by heartburn, nausea, diarrhoea and constipation. Conclusions Through adequate training community pharmacy internship students get competencies and are capable of detecting and reporting ADRs through direct questions to drug users. Copyright © 2010 John Wiley & Sons, Ltd.

A method for simultaneous bioanalysis of the three cytotoxic drugs cytosine arabinoside, daunorubicin and etoposide in human plasma was developed and validated. A HPLC method with ultra-violet and fluorescence detection, preceded by mixed-mode cation-exchange solid phase extraction sample preparation, was used for the quantification of the analytes. The assay was used for the simultaneous measurement of cytosine arabinoside, daunorubicin and etoposide with linearity in the ranges of 13–1500 ng/mL, 15–1000 ng/mL and 52.5–3500 ng/mL, respectively. The chromatographic run-time was 15.5 min. The overall precision (% relative standard deviation) was within 0.2–13.5% and the recovery ranged between 86.1% and 110.1% for the three drugs at all concentrations tested. Plasma samples were stable for at least two months when stored at −20 °C. The method was successfully applied to quantification of the three drugs in blood samples from patients undergoing induction treatment for acute myeloid leukaemia, thus demonstrating its suitability for clinical studies.

Background Various approaches have been made over the years to classify psychotic patients according to inadequate treatment response, using terms such as treatment resistant or treatment refractory . Existing classifications have been criticized for overestimating positive symptoms; underestimating residual symptoms, negative symptoms, and side effects; or being to open for individual interpretation. The aim of this study was to present and evaluate a new method of classification according to treatment response and, thus, to identify patients in functional remission. Method A naturalistic, cross-sectional study was performed using patient interviews and information from patient files. The new classification method CANSEPT, which combines the Camberwell Assessment of Need rating scale, the Udvalg for Kliniske Undersogelser side effect rating scale (SE), and the patient's previous treatment history (PT), was used to group the patients according to treatment response. CANSEPT was evaluated by comparison of expected and observed results. Results In the patient population (n = 123), the patients in functional remission, as defined by CANSEPT, had higher quality of life, fewer hospitalizations, fewer psychotic symptoms, and higher rate of workers than those with the worst treatment outcome. Conclusion In the evaluation, CANSEPT showed validity in discriminating the patients of interest and was well tolerated by the patients. CANSEPT could secure inclusion of correct patients in the clinic or in research.

Background and objective: Preterm and term newborn infants show wide interindividual variability (IIV) in pharmacokinetic parameters of gentamicin. More extensive knowledge and use of predictive covariates could lead to faster attainment of therapeutic concentrations and a reduced need for concentration monitoring. This study was performed to characterize the population pharmacokinetics of gentamicin in preterm and term neonates and to identify and quantify relationships between patient characteristics and IIV. A secondary aim was to evaluate cystatin C as a marker for gentamicin clearance in this patient population. Methods: Data were collected in a prospective study performed in the Neonatal Intensive Care Unit at the University Children’s Hospital, Uppsala, Sweden. Population pharmacokinetic modelling was performed using nonlinear mixed-effects modelling (NONMEM) software. Bodyweight was included as the primary covariate according to an allometric power model. Other evaluated covariates were age (postmenstrual age, gestational age [GA], postnatal age [PNA]), markers for renal function (serum creatinine, serum cystatin C) and concomitant medication with cefuroxime, vancomycin or indometacin. Covariate-parameter relationships were explored using a stepwise covariate model building procedure. The predictive performance of the developed model was evaluated using an independent external dataset for a similar patient population. Results: Sixty-one newborn infants (GA range 23.3–42.1 weeks, PNA range 0–45 days) were enrolled in the study. In total, 894 serum gentamicin samples were included in the analysis. The concentration-time profile was described using a three-compartment model. Gentamicin clearance increased with the GA and PNA (included in a nonlinear fashion). The GA was also identified as having a significant influence on the central volume of distribution, with a preterm neonate having a larger central volume of distribution per kilogram of bodyweight than a term neonate. Cystatin C and creatinine were not correlated with gentamicin clearance in this study population. The external dataset was well predicted by the developed model. Conclusion: Bodyweight and age (GA and PNA) were found to be major factors contributing to IIV in gentamicin clearance in neonates. Based on these data, cystatin C and serum creatinine were not correlated with gentamicin clearance and therefore not likely to be predictive markers of renal function in this patient population. Based on predictions from the developed model, preterm neonates do not reach targeted peak and trough gentamicin concentrations after a standard dosage regimen of 4 mg/kg given once daily, suggesting a need for higher loading doses and prolonged dosing intervals in this patient population.

Defined daily doses per day and 103 inhabitants (DDD/day/103 inh.) of the day different types of antiparkinson agents have been compared in the period 1975–1979 for Norway, Sweden, Denmark and Finland. A marked increase in the utilization of L-DOPA containing drugs has taken place especially in Sweden following the introduction of the “combined drugs” (L-DOPA + decarboxylase inhibitor). Statistically, nearly all patients with parkinsonism in Sweden have since 1977 been treated with L-DOPA, while in the other nordic countries about 10% of the patients are not on this therapy. These data are discussed in relation to the current concept of pharmacotherapy of parkinsonism. Further, many patients treated with neuroleptic drugs do in addition take anticholinergic agents. Drug utilization figures indicate this method of treatment to be most common in Denmark and Sweden.

The intracerebral kinetics of [11C]-labelled L-3,4-dihydroxyphenylalanine, L-DOPA, was investigated in rhesus monkeys by positron emission tomography (PET). Through the labelling of the L-DOPA molecule in different positions and observation of a series of pharmacological challenges it was possible to establish that the kinetic conversion of the radiotracer in the striatum represents the process of decarboxylation to [11C]-labelled dopamine. The rate constant for this process can be estimated using a two-compartment model. The use of [11C]-L-DOPA and PET will thus provide a possibility for in vivo studies of blood-brain barrier transport of the amino acid as well as for the estimation of the ability for brain tissue to decarboxylate the tracer by the action of aromatic L-amino acid decarboxylase.

Many patients with psychotic symptoms respond poorly to treatment. Factors possibly affecting treatment response include the presence of polymorphisms in genes coding for various receptor populations, drug-metabolizing enzymes or transport proteins.To investigate whether genetic polymorphisms could be indicators of treatment response to antipsychotic drugs. The genes of interest were the dopamine D2 receptor gene (DRD2), the serotonin 2A and 2C receptor genes (HTR2A and HTR2C), the P-glycoprotein gene (ABCB1 or MDR1) and the drug-metabolizing cytochrome P450 2D6 gene (CYP2D6).Data for this naturalistic, cross-sectional study of patients requiring antipsychotic drugs and attending the Psychosis Outpatient Care clinic in Jönköping, Sweden were obtained from patient interviews, blood samples and information from patient files. Blood samples were genotyped for DRD2 Taq1 A, Ins/Del and Ser311Cys, HTR2A T102C, HTR2C Cys23Ser, ABCB1 1236CT, 2677GT/A, 3435CT and genetic variants of CYP2D6. The patients (n=116) were grouped according to the CANSEPT method regarding significant social and clinical needs and significant side effects.Patients on olanzapine homozygous for ABCB1 3435T, had more significant social and clinical needs than others. Patients with one or two DRD2 Taq1 A1 alleles had a greater risk of significant side effects, particularly if they were male, Caucasian, had a schizophrenic or delusional disorder or were taking strong dopamine D2-receptor antagonistic drugs.If these results are confirmed, patients carrying the DRD2 Taq1 A1 allele would benefit from using drugs without strong dopamine D2 receptor antagonistic properties.

Modelling the distribution of invasive alien species is widely used for predicting future dispersal, response to climate change, and effects of management, but little information is available on the scale dependence of spatial models. This study is focused on Heracleum mantegazzianum, a problematic invasive plant in central and north-western Europe. The main objective was to model the current distribution of this species at national (43,000 km 2 ) and regional scale (4900 km 2 ) using autologistic regression with a Danish data set. Presence-absence data were used in a grid system with 5 x 5 km 2 or 2 x 2 km 2 as basic units. To avoid misleading presence-absence models and unreliable probability values due to unbalanced data, the prevalence was used as cut-off value, and a favourability function was applied to the model predictions. The national model showed a widespread distribution of H. mantegazzianum with highest habitat suitability in the eastern and northern parts of the country where human population density is high, winters more severe and/or loamy soils more common. At a regional scale the distribution of H. mantegazzianum is associated with alluvial sand cover, high human population density, spring precipitation, and presence of the species in neighbour grid units. The observed widespread national distribution is likely the result of anthropogenic spread of this ornamental plant, while the locally clumped distribution suggests that H. mantegazzianum naturally spreads mainly over short distances. The current distribution in Denmark resembles an intermediate invasion stage where long-distance dispersal is less important, while spread from suitable neighbour habitats is significant. The study demonstrates that the favourability function leads to improved mapping standards for invasive species.

Although numerous studies have dealt with changes in blood brain-derived neurotrophic factor (BDNF), methodological issues about BDNF measurements have only been incompletely resolved. We validated BDNF ELISA with respect to accuracy, reproducibility and the effect of storage and repeated freezing cycles on BDNF concentrations. Additionally, the effect of demographic characteristics in healthy subjects on BDNF was verified. Whole blood and serum was collected from 206 healthy subjects and a subgroup was genotyped for BDNF Val66Met polymorphism. The effect of age, gender, BDNF genotype and thrombocyte count on whole blood BDNF was assessed. The BDNF ELISA measurement was accurate, 91.6+/-3.0%, and showed high reproducibility, whereas inter-assay and intra-subject variations were modest, 8.4+/-5.2% and 17.5+/-14.1%, respectively. Storage of whole blood samples at 4 degrees C significantly decreased BDNF concentration, while repeated freezing cycles and storage at -20 degrees C was without any effect. Storage at -20 degrees C of serum, but not whole blood, was associated with a significant decrease in BDNF concentration. Women had significantly higher whole blood BDNF concentrations than men (18.6+/-1.3 ng/ml versus 16.5+/-1.4 ng/ml), and showed a right-skewed BDNF concentration distribution. No association between whole blood BDNF concentrations and thrombocyte count, age, or BDNF genotype was found. In conclusion, the BDNF ELISA assay determines whole blood BDNF accurately and with high reproducibility. Female gender is associated with higher whole blood BDNF concentrations whereas age, thrombocyte count and BDNF Val66Met polymorphism were un-associated.

Several research groups have demonstrated that under specific conditions, in vivo neuroreceptor binding techniques can be used to measure acute changes in the concentrations of endogenous transmitters in the vicinity of neuroreceptors. The aim of this study was to investigate whether [(11)C]-3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)-benzonitrile ([(11)C]DASB) binding to the plasma membrane serotonin transporter (SERT) in the rhesus monkey and rat brain decreased after a pharmacologically-induced increase in the interstitial serotonin (5HT) concentration. Three rhesus monkeys were given repeated single boluses of [(11)C]DASB in sequential positron emission tomography (PET) experiments. Rats were given the tracer as a bolus dose plus a constant infusion. In vivo binding in both models was studied before and after presumably having increased interstitial 5HT concentrations using tranylcypromine (TCP), which inhibits the enzyme (monoamine oxidase, MAO), that degrades 5HT. The rat brain tissue was analyzed using high-performance liquid chromatography (HPLC) to determine the proportion of the PET signal comprising unchanged [(11)C]DASB. The binding of [(11)C]DASB in the thalamus decreased in both rhesus monkeys and rats after TCP administration. The possibility of using [(11)C]DASB as a tool for monitoring changes in endogenous serotonin concentrations merits further investigation.

Molecular imaging with positron emission tomography (PET) has revolutionized the study of brain physiology. The facilitated diffusion of large neutral L-amino acids (LNAA) across the blood–brain barrier (BBB) is mediated by the LAT1 carrier in the capillary endothelium. A number of substrates for this carrier have been labeled with fluorine-18 and tested as PET oncology tracers; compounds such as [18F]fluoro-ethyltyrosine enter the brain, but are not metabolized. Over-expression of LAT1 and other transporter systems in some tumors results in elevated LNAA uptake relative to the physiological background. Dynamic PET with the endogenous LNAA [11C]tyrosine PET reveals not just reversible BBB transport but also irreversible trapping in brain protein, which can be quantified using linear graphic analysis. In theory, [11C]tyrosine PET might also reveal a signal related to the synthesis of dopamine in nigrostriatal terminals, but in practice, the neurotransmitter pathway cannot be visualized against the background of protein synthesis. However, the trapping of [18F]-fluorodopa (FDOPA) and other aromatic L-amino acid decarboxylase (AAADC) substrates reveals the integrity of the nigrostriatal dopamine pathway, without interference from a background of physiological protein synthesis. The serotonin precursor [11C]-5-hydroxytryptophan seems to be decarboxylated preferentially by AAADC expressed in serotonin fibers; in theory, specificity for visualizing the serotonin pathway is to be obtained with α-[11C]methyltryptophan ([11C]AMT), which is not a substrate for protein synthesis. However, the rate of conversion of this tracer to α-[11C]methyserotonin in serotonin neurons of living brain is low, such that its quantitation in PET studies is challenging. The issue of conversion is also central to prospects for molecular imaging of the kynurenine pathway in PET studies with [11C]AMT.

Study objectives. Cancer-related fatigue (CRF) is frequently reported by cancer patients receiving cytotoxic drugs. The specific mechanism of CRF in cancer patients is not completely known. In recent years, convincing evidence supports the management of fatigue with physical exercise. This study investigated a recommendation that physical activity, eg, a 30-minute daily walk, would decrease fatigue in cancer patients receiving cytotoxic drugs at an outpatient ward. Method. In total, 89 patients were interviewed about their fatigue and were asked to complete a questionnaire, the Fatigue Symptom Inventory (FSI), once a week over several treatment cycles of cytotoxic drugs. On inclusion, all patients received similar information about fatigue. After randomization, information about the positive effects of exercise was given to half of the patients after one cycle of cytotoxic drugs, and to the remaining patients after two cycles of cytotoxic drugs. Results. A total of 74 patients completed the study and returned useable questionnaires. The fatigue prevalence was 89% after one cytotoxic drug cycle. According to the FSI ratings, the group who received information about physical exercise after one cycle scored significantly lower ratings than the other group throughout the study (P=0.034). The patient interviews confirmed that physical activity helped them to better battle fatigue. Intensity of other symptoms and side effects from cytotoxic drugs closely paralleled the fatigue ratings. Conclusion. Fatigue was commonly found in the study population. Though small improvements followed physical exercise, results pointed towards the fact that information and exercise may support patients to combat fatigue. Early and frequent information would probably support patients to better combat fatigue by physical exercise.

The two-tissue compartment model, including irreversible trapping in the second compartment (2TCM) is used to describe the kinetics of 5-Hydroxy-L-[beta-(11)C]-tryptophan ([(11)C]HTP), a radioligand used in positron emission tomography (PET) for probing the second enzymatic step in the biosynthesis of serotonin. In this study, we examined the capacity of the model to track pharmacological changes in this biological process. We also investigated the potential loss of [(11)C]HTP-derived radioactivity during a PET study, since loss should be negligible not to alter quantification. Six rhesus monkeys were investigated using bolus [(11)C]HTP/PET methodology before and after pharmacological intervention. The second enzymatic step in serotonin synthesis was inhibited using the aromatic L-amino acid decarboxylase inhibitor NSD1015 (10 mg/kg). The extent of [(11)C]-derived radioactivity loss from the brain was studied by inhibition of the enzyme responsible for formation of the tissue metabolite, monoamine oxidase A, using clorgyline (2 mg/kg). After NSD1015, the uptake of [(11)C]HTP-derived radioactivity was increased in all the investigated brain regions, while the parameter used to reflect decarboxylase activity, the net accumulation rate constant (K(acc)), was decreased by 37% in the striatum, compared with baseline. Pretreatment with clorgyline did not change the brain uptake of [(11)C]HTP-derived radioactivity or K(acc). This study demonstrates that the 2TCM for [(11)C]HTP/PET is able to detect changes occurring during alteration of the biological process (i.e., the conversion of HTP to serotonin). Elimination of the radiotracer metabolite [(11)C]HIAA from the brain may be considered negligible if the PET study is limited to 60 min.

Twelve children, all boys, aged 4 to 7 years, with a diagnosis of autistic disorder and low concentrations of spinal 6R-l-erythro-5,6,7,8-tetrahydrobiopterin (tetrahydrobiopterin) were selected to participate in a double-blind, randomized, placebo-controlled, crossover study. The children received a daily dose of 3 mg tetrahydrobiopterin per kilogram during 6 months alternating with placebo. Treatment-induced effects were assessed with the Childhood Autism Rating Scale every third month. The results showed small nonsignificant changes in the total scores of Childhood Autism Rating Scale after 3- and 6-month treatment. Post hoc analysis looking at the 3 core symptoms of autism, that is, social interaction, communication, and stereotyped behaviors, revealed a significant improvement of the social interaction score after 6 months of active treatment. In addition, a high positive correlation was found between response of the social interaction score and IQ. The results indicate a possible effect of tetrahydrobiopterin treatment.

The serotonin transporter radioligand [11C]-3-amino-4-(2-dimethylaminomethylphenylsulfanyl)-benzonitrile, or [11C]DASB, was examined in order to assess its potential for measuring fluctuations in endogenous serotonin concentrations with positron emission tomography. Binding characteristics of [11C]DASB and the propensity for serotonin to displace the tracer were explored in rat brain homogenates. Experiments showed that serotonin displaced [11C]DASB in vitro. Ex vivo experiments performed after tranylcypromine injection (3 or 15 mg/kg) showed a dose-dependent trend in radioactivity uptake and suggested that serotonin may compete with [11C]DASB for transporter binding.

Plant distribution borders are key features to characterise the ecological niche of a species and to monitor effects of climate change. Here we focus on an evergreen small tree, Ilex aquifolium, which reaches its north-eastern range edge in Denmark. Our main objectives are to describe and to model the current distribution of the species, to identify the most important climatic and land use factors which shape this distribution pattern, and to analyse the species' habitat requirements. For this purpose we used data from a national mapping project, complemented by information from forest owners. The distribution and abundance of I. aquifolium in Denmark have markedly changed during the past 40 years. It is now found in almost all districts, although the centres of abundance still coincide with the historical records. Our model shows lower habitat suitability for the species in northern and eastern districts, where winters are more severe and spring precipitation is lower. To a lesser extent, land use influences I. aquifolium occurrence, but it is more common in areas with a high proportion of forests and/or urban sites. The analysis of habitat requirements supports these results, since I. aquifolium occurs mainly as a forest species in deciduous stands, on relatively nutrient-rich moist soils, and under moderately high light conditions. However, some records may be the product of seed dispersal from planted individuals nearby. The results suggest that the range edge of the species has moved at least 100 km east within half a century. Since I.aquifolium is sensitive to winter frost, this change in distribution may be due to increasingly mild winter temperatures.

During the period February 1997 to April 2000, 15 patients with clinical symptoms of Creutzfeldt-Jakob disease (CJD) were referred to Uppsala University PET Centre. Positron emission tomography (PET) was performed to detect characteristic signs of the disease, e.g. neuronal death and/or astrocytosis in the brain. The examinations were performed in one session starting with oxygen-15 labelled water scan to measure regional cerebral blood flow, followed by imaging with the monoamine oxidase B inhibitor N-[(11)C-methyl]- L-deuterodeprenyl (DED) to assess astrocytosis in the brain and finally imaging with fluor-18 2-fluorodeoxyglucose (FDG) to assess regional cerebral glucose metabolism (rCMR(glu)) [corrected]. Nine of the patients fulfilled the clinical criteria of probable CJD. In eight of them, FDG and DED imaging revealed, in comparison with normal controls, a typical pattern characterized by a pronounced regional decrease (2SD) in glucose brain metabolism, indicative of neuronal dysfunction; this was accompanied by a similar increase (2SD) in DED binding, indicating astrocytosis. These changes were most pronounced in the cerebellum and the frontal, occipital and parietal cortices, whereas the pons, the thalamus and the putamen were less affected and the temporal cortex appeared unaffected. The cerebral blood flow showed a pattern similar to that observed with FDG. In the ninth patient, analysis with DED was not possible. The diagnosis of definite CJD according to international consensus criteria was confirmed in six of these patients. In one patient with probable CJD, protease-resistant prion protein (PrPres) could not be demonstrated. In two patients with probable CJD, autopsy was not allowed. Computed tomography and magnetic resonance imaging, performed in four and seven of these nine patients respectively, showed unspecific, mainly atrophic changes. In six other patients, the PET examinations gave a different pattern. In three of them, high rCMR(glu) was noticed in parts of the brain, particularly in the temporal lobes and basal ganglia, which could suggest encephalitis. One of the patients had Sjögren's syndrome, one had paraneoplastic limbic encephalitis and the third recovered spontaneously. In the other three patients, the DED binding was normal despite a hypometabolic glucose pattern. In conclusion, the PET findings obtained using DED and FDG paralleled neuropathological findings indicating neuronal dysfunction and astrocytosis, changes that are found in CJD.

The effects on the binding to cholinergic and dopaminergic receptors in the brain during continuous intravenous infusion of the muscarinic cholinergic receptor agonist milameline (CI-979) were studied in the rhesus monkey by means of positron emission tomography. Binding to milameline cholinergic receptors was quantified using the muscarinic receptor antagonist [11C]-N-methyl-4-piperidinylbenzilate ([11C]NMP), and the effects on nicotine receptor binding were measured with (S)-[11C-methyl]nicotine. Changes in the binding of the D2 dopamine receptor antagonist [11C]raclopride were measured as well. The binding of [11C]NMP increased in most brain regions with the infusion of increasing doses of milameline from 0.5 to 10 µg/kg/h. (S)-[11C-methyl]nicotine binding was unchanged or increased somewhat. Binding of [11C]raclopride to the D2 dopaminergic receptors in the striatum of the brain increased by 10 ± 4% following 2 µg/kg/h of milameline. The results suggest a possible action of milameline both on presynaptic muscarinic receptor subtypes as well as dopamine levels dependent on the receptor reserve of the muscarinic receptor subtypes.

Hydrophilic drugs particularly those with low plasma protein binding may accumulate in third-space fluid in the body. Cytotoxic drugs like methotrexate (MTX) cause damage in the tissue, and evacuation of the third-space fluid in pleura is strongly recommended before new dosing. Pemetrexed (PEM) is a multi-targeted antifolate similar to MTX approved for the treatment for malignant pleural mesothelioma and non-small cell lung cancer. Current recommendations for patients receiving treatment with PEM prescribe draining of the pleural fluid. This is based upon the recommendations for MTX and not directly to any specific findings relating to PEM. The recommendations are the same because PEM is an analogue of MTX; the molecular structures and pharmacokinetic parameters are similar. However, since draining the pleural fluid is painful and cancer patient are particularly susceptible to infection subsequently, it is relevant to examine the recommendations for PEM explicitly. Eight patients treated with a 500 mg/m2 PEM combined with platinum salt were examined. Plasma samples were first collected in relation to the start of PEM infusion. Thereafter, plasma and pleura samples were taken at various times after drug infusion from each patient; in two patients, sampling was done twice but on different occasions. The quantitative determination of PEM was performed with reversed-phase high-performance liquid chromatography, and sample preparation was performed using protein precipitation with perchloric acid. Pharmacokinetic analysis was performed using a non-compartment method as well a two-compartment model. The results were calculated from 10 samples taken from eight patients, where data from one patient point were excluded as the patient had impaired renal function, and three samples were reported as below limit of quantification. The plasma PEM pharmacokinetics calculated showed an elimination half-life (t ½ elimination) of 3.2 h and distribution half-life (t ½-distribution) of 6 min. Clearance (CL) was 5.1 L/h, central volume of distribution (V central) 23.2 L and peripheral volume distribution (V peripheral) 10.6 L, and the area under the curve was 186 μg h/mL. Using non-compartment methods, an elimination half-life of 3.1 h and an apparent CL of 3.2 L/h were measured, whereas an apparent steady-state volume became 14.2 L. The pleura concentrations were only half of simultaneous plasma concentrations, and elimination half-life was 3.15 h. Pemetrexed is not likely to accumulate in the pleural fluid, and evacuation of fluid might not be necessary. Further investigation is needed to recommend no drainage of the fluid, i.e., in patients with renal impairment.

Positron emission tomography (PET) has the potential to study the biosynthesis and release of serotonin (5HT) at brain serotonergic neurons. PET requires probe compounds with specific attributes to enable imaging and quantification of biological processes. This section focuses on probes to measure seroonin synthesis rate. Knowledge of altered 5HT synthesis and release in disease states may furnish basis for effective pharmacotherapy that may improve the care of psychiatric and neurological disease.