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Background.The role of angiotensin II (Ang II) in the systemic and renal responses to acute nitric oxide (NO) synthesis inhibition has not been studied in detail in healthy humans. The purpose of the present study was to investigate the effects of Ang II receptor blockade on the systemic and renal response to acute treatment with Ng-monomethyl-L-arginine (L-NMMA) in healthy subjects. [ABSTRACT FROM PUBLISHER]

Background and Purpose: Most patients with isolated rapid eye movement sleep behaviour disorder (iRBD) progress to a parkinsonian alpha-synucleinopathy. However, time to phenoconversion shows great variation. The aim of this study was to investigate whether cholinergic and dopaminergic dysfunction in iRBD patients was associated with impending phenoconversion., Methods: Twenty-one polysomnography-confirmed iRBD patients underwent baseline 11 C-donepezil and 6-Fluoro-( 18 F)-l-3,4-dihydroxyphenylalanine ( 18 F-DOPA) positron emission tomography (PET). Potential phenoconversion was monitored for up to 8 years. PET images were analysed according to patients' diagnoses after 3 and 8 years using linear regression. Time-to-event analysis was made with Cox regression, dividing patients into low and high tracer uptake groups., Results: Follow-up was accomplished in 17 patients. Eight patients progressed to either Parkinson's disease (n = 4) or dementia with Lewy bodies (n = 4), while nine remained non-phenoconverters. Compared with non-phenoconverters, 8-year phenoconverters had lower mean 11 C-donepezil uptake in the parietal (p = 0.032) and frontal cortex (p = 0.042), whereas mean 11 C-donepezil uptake in 3-year phenoconverters was lower in the parietal cortex (p = 0.005), frontal cortex (p = 0.025), thalamus (p = 0.043) and putamen (p = 0.049). Phenoconverters within 3 years and 8 years had lower 18 F-DOPA uptake in the putamen (p < 0.001). iRBD patients with low parietal 11 C-donepezil uptake had a 13.46 (95% confidence interval 1.42;127.21) times higher rate of phenoconversion compared with those with higher uptake (p = 0.023). iRBD patients with low 18 F-DOPA uptake in the most affected putamen were all phenoconverters with higher rate of phenoconversion (p = 0.0002)., Conclusions: These findings suggest that cortical cholinergic dysfunction, particularly within the parietal cortex, could be a biomarker candidate for predicting short-term phenoconversion in iRBD patients. This study aligns with previous reports suggesting dopaminergic dysfunction is associated with forthcoming phenoconversion., (© 2024 The Author(s). European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Introduction: Multiple sclerosis (MS) causes a broad range of symptoms, with physical function being one of the most disabling consequences according to patients themselves. Exercise effectively improves lower extremity physical function. Nonetheless, it is unknown which exercise modality is most effective and it remains challenging to keep persons with MS adhering to exercise over a longer period. Therefore, the present study aims to investigate how exercise booster sessions (EBS) influence the sustainability of exercise-induced effects on physical function, and furthermore, to investigate which exercise modality (aerobic training or resistance training) is most effective in terms of improving physical function., Materials and Methods: This study is a multi-arm, parallel-group, open-label multicentre randomised controlled trial investigating the effects of EBS. Participants (n=150) are initially randomised to 12 weeks of either resistance training+usual care, aerobic training+usual care or usual care. After 12 weeks of intervention, participants in the exercise groups will again be randomised to either EBS+usual care or usual care during a 40-week follow-up period. The primary outcome is physical function (composite score based on 6-min walk test and five-time sit to stand), and the secondary outcomes are fatigue, cognition, physical activity, symptoms of depression and quality of life., Ethics and Dissemination: The study is approved by the Central Denmark Region Committees on Health Research Ethics (1-10-72-237-21) and is registered at the Danish Data Protection Agency (2016-051-000001) and at Clinicaltrials.gov (NCT04913012). All study findings will be published in scientific peer-reviewed journals and presented at scientific conferences., Trial Registration Number: NCT04913012., Competing Interests: Competing interests: LT-M, HD, RR, KBS and JL-J declare no conflict of interest. LGH has received travel grants and/or teaching honorary from Biogen and Sanofi Genzyme. UD has received research support, travel grants and/or teaching honorary from Biogen, Merck Serono, Novartis, Bayer Schering and Sanofi Aventis as well as honoraria from serving on scientific meetings of Biogen and Sanofi Genzyme. HHC reports non-financial support from Merck, non-financial support from Teva, non-financial support from Biogen, non-financial support from Roche and non-financial support from Novartis outside the submitted work and personal support from the Warwara Larsen Foundation. FS has served on scientific advisory boards for, served as consultant for, received support for congress participation or received speaker honoraria from Alexion, Biogen, Bristol Myers Squibb, Lundbeck, Merck, Novartis, Roche and Sanofi Genzyme. His laboratory has received research support from Biogen, Merck, Novartis, Roche and Sanofi Genzyme. VP has received travel grants from Merck and Sanofi and research support from Roche. JRC has received speaker honoraria from Biogen. RR has served on scientific advisory boards, received speaker honoraria and received support for congress participation from Merck, Sanofi, Roche, Medtronic and Ipsen. TS has served on scientific advisory boards for, served as consultant for, received support for congress participation or received speaker honoraria from Biogen, Merck, Novartis, Roche and Sanofi. TS received unrestricted research grants to his research institution from Biogen, Merck and Roche, and is currently engaged in sponsor-initiated research projects by Eisai, Lundbeck, Roche and Sanofi., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Using 11 C-(R)-PK11195-PET, we found increased microglia activation in isolated REM sleep behavior disorder (iRBD) patients. Their role remains to be clarified., Objectives: The objective is to assess relationships between activated microglia and progression of nigrostriatal dysfunction in iRBD., Methods: Fifteen iRBD patients previously scanned with 11 C-(R)-PK11195 and 18 F-DOPA-PET underwent repeat 18 F-DOPA-PET after 3 years. 18 F-DOPA K i changes from baseline were evaluated with volumes-of-interest and voxel-based analyses., Results: Significant 18 F-DOPA K i reductions were found in putamen and caudate. Reductions were larger and more widespread in patients with increased nigral microglia activation at baseline. Left nigral 11 C-(R)-PK11195 binding at baseline was a predictor of 18 F-DOPA K i reduction in left caudate (coef = -0.0426, P = 0.016)., Conclusions: Subjects with increased baseline 11 C-(R)-PK11195 binding have greater changes in nigrostriatal function, suggesting a detrimental rather than protective effect of microglial activation. Alternatively, both phenomena occur in patients with prominent nigrostriatal dysfunction without a causative link. The clinical and therapeutic implications of these findings need further elucidation. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Good sexual health promotes quality of life and coping skills, and this also applies to older adults. This clinical review article presents updated knowledge on older adults' sexuality, normal challenges related to ageing and conjugal relationships, and sexual challenges caused by chronic diseases, adverse effects of medications, and cognitive failure. The review describes measures to improve sexual health. Healthcare personnel should take the initiative to talk about sexual health with older adults.

Background and Objectives: We aimed to evaluate the mortality of patients with AQP4 antibody-seropositive (AQP4-Ab+) neuromyelitis optica spectrum disorder (NMOSD) in Denmark compared with that in the general population., Methods: We identified patients with AQP4-Ab+ NMOSD fulfilling the 2015 International Panel for Neuromyelitis Optica Diagnosis (IPND) criteria from multiple sources (laboratories and the Danish Multiple Sclerosis Registry). We obtained detailed information about patients from hospital records and about the general population matched on age, sex, and calendar year from Statistics Denmark. We calculated standardized mortality ratio (SMR), excess number of deaths per 1,000 person-years (EDR), and life expectancies compared with those of the matched general population. We examined predictive factors of mortality and the cause of death., Results: Of 66 patients with AQP4-Ab+ NMOSD between 2008 and 2020, 15 died. Overall, the SMR was 2.54 (95% CI 1.47-4.09), and the EDR was 16.8 (95% CI 4.6-34.3). The median life expectancy for patients with AQP4-Ab+ NMOSD was 64.08 years (95% CI 53.02-83.9), compared with 83.07 years for the general population. Risk of death over time was increased in the patient population with a hazard ratio (HR) of 2.22 (1.34-3.68; p = 0.002). The cause of death was directly related to NMOSD in 93% of the cases. The age at disease onset was an independent predictor of death (HR 1.042; 95% CI 1.006-1.079; p = 0.02)., Discussion: AQP4-Ab+ NMOSD is associated with increased mortality and shorter life expectancy compared with that in the general population, underlining the need for highly effective treatment approaches.

Background: Reduced cortical acetylcholinesterase activity, as measured by 11 C-donepezil positron emission tomography (PET), has been reported in patients with isolated rapid eye movement (REM) sleep behavior disorder (iRBD). However, its progression and clinical implications have not been fully investigated. Here, we explored the relationship between longitudinal changes in brain acetylcholinesterase activity and cognitive function in iRBD., Methods: Twelve iRBD patients underwent 11 C-donepezil PET at baseline and after 3 years. PET images were interrogated with statistical parametric mapping (SPM) and a regions of interest (ROI) approach. Clinical progression was assessed with the Movement Disorder Society-Unified Parkinson's Disease Rating Scale-Part III (MDS-UPDRS-III). Cognitive function was rated using the Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA)., Results: From baseline to follow-up, the mean 11 C-donepezil distribution volume ratio (DVR) decreased in the cortex (p = 0.006), thalamus (p = 0.013), and caudate (p = 0.013) ROI. Despite no significant changes in the group mean MMSE or MoCA scores being observed, individually, seven patients showed a decline in their scores on these cognitive tests. Subgroup analysis showed that only the subgroup of patients with a decline in cognitive scores had a significant reduction in mean cortical 11 C-donepezil DVR., Conclusions: Our results show that severity of brain cholinergic dysfunction in iRBD patients increases significantly over 3 years, and those changes are more severe in those with a decline in cognitive test scores., (© 2023 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Information on the pharmacokinetics (PK) and pharmacodynamics (PD) of orally administered cannabis-based medicine (CBM) in capsule formulation in patient populations is sparse. In this exploratory study, we aimed to evaluate the PK and PD in a probable steady state of CBM in neuropathic pain and spasticity in a population of patients with multiple sclerosis (MS). Of 134 patients participating in a randomized, double-blinded, placebo-controlled, trial, 23 patients with MS (17 female) mean age 52 years (range 21-67) were enrolled in this substudy. They received oral capsules containing Δ 9 -tetrahydrocannabinol (THC, n = 4), cannabidiol (CBD, n = 6), a combination (THC&CBD, n = 4), or placebo (n = 9). Maximum doses were 22.5 mg (THC) and 45 mg (CBD) a day divided into three administrations. PD parameters were evaluated for pain and spasticity. Blood samples were analyzed using an ultra-high-performance liquid chromatography-tandem mass spectrometer after protein precipitation and phospholipid removal. PK parameters were estimated using computerized modeling. The variation in daily dose and PK between individuals was considerable in a steady state, yet comparable with previous reports from healthy controls. Based on a simulation of the best model, the estimated PK parameters (mean) for THC (5 mg) were C max 1.21 ng/mL, T max 2.68 h, and half-life 2.75 h, and for CBD (10 mg) were C max 2.67 ng/mL, T max 0.10 h, and half-life 4.95 h, respectively. No effect was found on the PD parameters, but the placebo response was considerable. More immediate adverse events were registered in the active treatment groups compared with the placebo group., (© 2023 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Importance: Ocrelizumab, a humanized monoclonal antibody targeted against CD20+ B cells, reduces the frequency of relapses by 46% and disability worsening by 40% compared with interferon beta 1a in relapsing-remitting multiple sclerosis (MS). Rituximab, a chimeric monoclonal anti-CD20 agent, is often prescribed as an off-label alternative to ocrelizumab., Objective: To evaluate whether the effectiveness of rituximab is noninferior to ocrelizumab in relapsing-remitting MS., Design, Setting, and Participants: This was an observational cohort study conducted between January 2015 and March 2021. Patients were included in the treatment group for the duration of study therapy and were recruited from the MSBase registry and Danish MS Registry (DMSR). Included patients had a history of relapsing-remitting MS treated with ocrelizumab or rituximab, a minimum 6 months of follow-up, and sufficient data to calculate the propensity score. Patients with comparable baseline characteristics were 1:6 matched with propensity score on age, sex, MS duration, disability (Expanded Disability Status Scale), prior relapse rate, prior therapy, disease activity (relapses, disability accumulation, or both), magnetic resonance imaging lesion burden (missing values imputed), and country., Exposure: Treatment with ocrelizumab or rituximab after 2015., Main Outcomes and Measures: Noninferiority comparison of annualized rate of relapses (ARRs), with a prespecified noninferiority margin of 1.63 rate ratio. Secondary end points were relapse and 6-month confirmed disability accumulation in pairwise-censored groups., Results: Of the 6027 patients with MS who were treated with ocrelizumab or rituximab, a total of 1613 (mean [SD] age; 42.0 [10.8] years; 1089 female [68%]) fulfilled the inclusion criteria and were included in the analysis (898 MSBase, 715 DMSR). A total of 710 patients treated with ocrelizumab (414 MSBase, 296 DMSR) were matched with 186 patients treated with rituximab (110 MSBase, 76 DMSR). Over a pairwise censored mean (SD) follow-up of 1.4 (0.7) years, the ARR ratio was higher in patients treated with rituximab than in those treated with ocrelizumab (rate ratio, 1.8; 95% CI, 1.4-2.4; ARR, 0.20 vs 0.09; P < .001). The cumulative hazard of relapses was higher among patients treated with rituximab than those treated with ocrelizumab (hazard ratio, 2.1; 95% CI, 1.5-3.0). No difference in the risk of disability accumulation was observed between groups. Results were confirmed in sensitivity analyses., Conclusion: In this noninferiority comparative effectiveness observational cohort study, results did not show noninferiority of treatment with rituximab compared with ocrelizumab. As administered in everyday practice, rituximab was associated with a higher risk of relapses than ocrelizumab. The efficacy of rituximab and ocrelizumab administered at uniform doses and intervals is being further evaluated in randomized noninferiority clinical trials.

Patients with multiple sclerosis (MS) and spinal cord injury (SCI) commonly sustain central neuropathic pain (NP) and spasticity. Despite a lack of consistent evidence, cannabis-based medicine (CBM) has been suggested as a supplement treatment. We aimed to investigate the effect of CBM on NP and spasticity in patients with MS or SCI. We performed a randomized, double-blinded, placebo-controlled trial in Denmark. Patients aged ≥18 years with NP (intensity >3, ≤9 on a numerical rating scale (NRS0-10) and/or spasticity (>3 on NRS0-10) were randomized to treatment consisting of either delta-9-tetrahydrocannabinol (THC), cannabidiol (CBD), a combination of THC&CBD in maximum doses of 22.5 mg, 45 mg and 22.5/45 mg per day, respectively, or placebo. A baseline registration was performed before randomization. Treatment duration was six weeks followed by a one-week phaseout. Primary endpoints were the intensity of patient-reported NP and/or spasticity. Between February 2019 and December 2021, 134 patients were randomized (MS n = 119, SCI n = 15), where 32 were assigned to THC, 31 to CBD, 31 to THC&CBD, and 40 to placebo. No significant difference was found for: mean pain intensity (THC 0.42 (-0.54-1.38), CBD 0.45 (-0.47-1.38) and THC&CBD 0.16 (-0.75-1.08)), mean spasticity intensity (THC 0.24 (-0.67-1.45), CBD 0.46 (-0.74-1.65), and THC&CBD 0.10 (-1.18-1.39), secondary outcomes (patient global impression of change and quality of life), or any tertiary outcomes. We aimed to include 448 patients in the trial; however, due to COVID-19 and recruitment challenges, fewer were included. Nevertheless, in this four-arm parallel trial, no effect was found between placebo and active treatment with THC or CBD alone or in combination on NP or spasticity in patients with either MS or SCI. The trial was registered with the EU Clinical Trials Register EudraCT (2018-002315-98).

Background: Cannabinoids have been suggested to alleviate frequently experienced symptoms of reduced mental well-being such as anxiety and depression. Mental well-being is an important subdomain of health-related quality of life (HRQoL). Reducing symptoms and maintaining HRQoL are particularly important in malignant primary brain tumor patients, as treatment options are often noncurative and prognosis remains poor. These patients frequently report unprescribed cannabinoid use, presumably for symptom relieve. As studies on brain tumor patients specifically are lacking, we performed a meta-analysis of the current evidence on cannabinoid efficacy on HRQoL and mental well-being in oncological and neurological patients. Methods: We performed a systematic PubMed, PsychINFO, Embase, and Web of Science search according to PRISMA guidelines on August 2 and 3, 2021. We included randomized controlled trials (RCTs) that assessed the effects of tetrahydrocannabinol (THC) or cannabidiol (CBD) on general HRQoL and mental well-being. Pooled effect sizes were calculated using Hedges g. Risk of bias of included studies was assessed using Cochrane's Risk of Bias tool. Results: We included 17 studies: 4 in oncology and 13 in central nervous system (CNS) disease. Meta-analysis showed no effect of cannabinoids on general HRQoL ( g =-0.02 confidence interval [95% CI -0.11 to 0.06]; p =0.57) or mental well-being ( g =-0.02 [95% CI -0.16 to 0.13]; p =0.81). Conclusions: RCTs in patients with cancer or CNS disease showed no effect of cannabinoids on HRQoL or mental well-being. However, studies were clinically heterogeneous and since many glioma patients currently frequently use cannabinoids, future studies are necessary to evaluate its value in this specific population.

Introduction: Most patients with isolated rapid eye movement sleep behaviour disorder (iRBD) convert to Parkinson's disease (PD), dementia with Lewy bodies, or multiple system atrophy within 15 years of diagnosis. Furthermore, iRBD patients develop non-motor symptoms similar to those of manifest PD patients and display dysfunction of the sympathetic and parasympathetic nervous system, comparable to that seen in PD. However, progression rates of autonomic dysfunction in iRBD have not been studied with objective measures in detail, which is the aim of this study., Methods: Twenty-two iRBD patients were included at baseline and 14 participated in follow-up after 3 years. Colonic transit time (CTT) was examined using radio opaque markers, colonic volume was defined on abdominal computed tomography (CT) scans, Iodine-123-metaiodobenzylguanidine ([123I]MIBG) scintigraphy was performed to assess cardiac sympathetic innervation, and 3,4-dihydroxy-6-(18F) fluoro-l-phenylalanine ([18F]FDOPA) positron emission tomography (PET) scan determined nigrostriatal dopamine storage capacity. All examinations were performed at baseline and after 3 years., Results: iRBD patients displayed increased CTT (p = 0.001) and colonic volume (p = 0.01) at follow-up compared to baseline. Furthermore, [123I]MIBG uptake and [18F]FDOPA uptake showed progressive reductions at follow-up (p = 0.02 and p = 0.002, respectively). No correlations were seen between changes in intestinal or cardiac measurements and dopaminergic function., Conclusion: Using objective markers, the present study documented that intestinal dysfunction and cardiac sympathetic degeneration worsen in the majority of iRBD patients over a 3-year period. The absent correlation between these markers and nigrostriatal dopaminergic dysfunction suggests that progressive gastrointestinal and cardiac dysfunction in iRBD is caused mainly by non-dopaminergic mechanisms., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Disease or acquired damage to the central nervous system frequently causes disabling spasticity and central neuropathic pain (NP), both of which are frequent in multiple sclerosis (MS) and spinal cord injury (SCI). Patients with MS and SCI often request treatment with cannabis-based medicine (CBM). However, knowledge about effects, side effects, choice of active cannabinoids (Δ9-tetrahydrocannabinol (THC), cannabidiol (CBD) alone or in combination), and doses of CBM remains limited. Using a double-blind, parallel design in a national multicenter cohort, this study examines the effect of CBM on spasticity and NP. Patients are randomized to treatment with capsules containing either THC, CBD, THC and CBD, or placebo. Primary endpoints are patient-reported pain and spasticity on a numerical rating scale. Other endpoints include quality of life and sleep, depression and anxiety, and relief of pain and spasticity. Side-effects of CBM are described. In a sub-study, the pharmacodynamics (PD) and pharmacokinetics (PK) of oral capsule CBM are examined. We expect that the study will contribute to the literature by providing information on the effects and side-effects of CBD, THC, and the combination of the two for central neuropathic pain and spasticity. Furthermore, we will describe the PD/PK of THC and CBD in a patient population.

During the prodromal period of Parkinson's disease and other α-synucleinopathy-related parkinsonisms, neurodegeneration is thought to progressively affect deep brain nuclei, such as the locus coeruleus, caudal raphe nucleus, substantia nigra, and the forebrain nucleus basalis of Meynert. Besides their involvement in the regulation of mood, sleep, behaviour, and memory functions, these nuclei also innervate parenchymal arterioles and capillaries throughout the cortex, possibly to ensure that oxygen supplies are adjusted according to the needs of neural activity. The aim of this study was to examine whether patients with isolated REM sleep behaviour disorder, a parasomnia considered to be a prodromal phenotype of α-synucleinopathies, reveal microvascular flow disturbances consistent with disrupted central blood flow control. We applied dynamic susceptibility contrast MRI to characterize the microscopic distribution of cerebral blood flow in the cortex of 20 polysomnographic-confirmed patients with isolated REM sleep behaviour disorder (17 males, age range: 54-77 years) and 25 healthy matched controls (25 males, age range: 58-76 years). Patients and controls were cognitively tested by Montreal Cognitive Assessment and Mini Mental State Examination. Results revealed profound hypoperfusion and microvascular flow disturbances throughout the cortex in patients compared to controls. In patients, the microvascular flow disturbances were seen in cortical areas associated with language comprehension, visual processing and recognition and were associated with impaired cognitive performance. We conclude that cortical blood flow abnormalities, possibly related to impaired neurogenic control, are present in patients with isolated REM sleep behaviour disorder and associated with cognitive dysfunction. We hypothesize that pharmacological restoration of perivascular neurotransmitter levels could help maintain cognitive function in patients with this prodromal phenotype of parkinsonism., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Synucleinopathies are neurodegenerative diseases with both central and peripheral immune responses. However, whether the peripheral immune changes occur early in disease and their relation to brain events is yet unclear. Isolated rapid-eye-movement (REM) sleep behavior disorder (iRBD) can precede synucleinopathy-related parkinsonism and provides a prodromal phenotype to study early Parkinson's disease events. In this prospective case-control study, we describe monocytic markers in a cohort of iRBD patients that were associated with the brain-imaging markers of inflammation and neuronal dysfunction. Using 11 C-PK11195 positron emission tomography (PET), we previously showed increased immune activation in the substantia nigra of iRBD patients, while 18 F-DOPA PET detected reduced putaminal dopaminergic function. Here we describe that patients' blood monocytic cells showed increased expression of CD11b, while HLA-DR expression was decreased compared to healthy controls. The iRBD patients had increased classical monocytes and mature natural killer cells. Remarkably, the levels of expression of Toll-like receptor 4 (TLR4) on blood monocytes in iRBD patients were positively correlated with nigral immune activation measured by 11 C-PK11195 PET and negatively correlated with putaminal 18 F-DOPA uptake; the opposite was seen for the percentage of CD163 + myeloid cells. This suggesting a deleterious role for TLR4 and, conversely, a protective one for the CD163 expression. We show an association between peripheral blood monocytes and brain immune and dopaminergic changes in a synucleinopathy-related disorder, thus suggesting a cross-talk among periphery and brain during the disease., Competing Interests: Competing interest statement: K.Ø. reports grants from The Danish Parkinson Association, The Danish Council for Independent Research, and the Lundbeck Foundation, and personal fees from Medtronic, UCB, Fertin Pharma, and AbbVie. D.J.B. reports grants from The Danish Council for Independent Research, the Lundbeck Foundation, The Danish Parkinson Association, European Union FP7 programme, and Alzheimer Research UK, and personal fees from GE Healthcare and Plexxikon. E.T. reports grants from The Michael J Fox Foundation and The Instituto de Salud Carlos III. N.P. reports grants from The Danish Council for Independent Research. M.R.-R. receives research support from NovoNordisk, Desiree og Niels Ydes Fond, The Danish Parkinson Association, The Danish Council for Independent Research, The Michael J Fox Foundation, and Aarhus University Research Foundation.

Introduction: In vivo PET studies in patients with isolated REM sleep behavior disorder (iRBD) have shown presence of neuroinflammation (microglial activation) in the substantia nigra, and reduced cortical acetylcholinesterase activity, suggestive of cholinergic dysfunction, that was more widespread in patients with poorer cognitive performances. This study aimed to explore whether reduced cortical acetylcholinesterase activity in iRBD is linked to microglial activation in the substantia innominata (SI), the major source of cholinergic input to the cortex., Methods: We used 11 C(R)-PK11195 and 11 C-Donepezil PET to assess levels of activated microglia and cholinergic function, respectively, in 19 iRBD patients. 11 C(R)-PK11195 binding potential (BP ND ) and 11 C-Donepezil distribution volume ratio (DVR) values were correlated using the Pearson statistic., Results: We found that a lower cortical 11 C-Donepezil DVR correlated with a higher 11 C(R)-PK11195 BP ND in the SI (r = -0.48, p = 0.04). At a voxel level, the strongest negative correlations were found in the frontal and temporal lobes., Conclusion: Our results suggest that reduced cortical acetylcholinesterase activity observed in our iRBD patients could be linked to the occurrence of neuroinflammation in the SI. Early modulation of microglial activation might therefore preserve cortical cholinergic functions in these patients., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Parkinson's disease is characterized by pathological α-synuclein accumulation and cell death, which has been hypothesized to originate in peripheral nerve terminals and subsequently spread via autonomic nerves. Supporting this, most Parkinson's disease patients experience autonomic non-motor symptoms such as constipation, often years prior to diagnosis., Objective: We aimed to study gastrointestinal transit time, colonic volume, and peristaltic movements in idiopathic REM Sleep Behavior Disorder patients, a prodromal marker of Parkinson's disease or Dementia with Lewy bodies., Methods: Twenty-two patients were included and compared to previously published data from Parkinson's disease patients and controls. Gastrointestinal transit time, computed tomography-based volume estimation, and colonic motility were performed as markers of gastrointestinal function and autonomic involvement. Subjective constipation symptoms were evaluated with two different questionnaires., Results: Gastrointestinal transit time was increased in 33% (p = 0.039) and colonic volume in 48% (p = 0.0049) of patients. Colonic transit time measured by the 3D-Transit system was increased in 70% (p = 0.0326) and the number of fast peristaltic colonic movements was reduced (p = 0.015). Mean small intestinal transit time was comparable to Parkinson's disease patients, although not significantly different compared to controls (p = 0.18). Subjective constipation symptoms were present in 18 or 41%, depending on type of questionnaire., Conclusions: Total gastrointestinal transit time, colonic volume, and 3D-Transit colonic transit time were significantly increased compared to controls, although not to the extent seen in medicated Parkinson's patients. Limited correlation was seen between subjective constipation and objective markers. The findings support that marked GI dysfunction is present in the early prodromal PD phase., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Accumulating evidence suggests that α-synuclein aggregates-a defining pathology of Parkinson's disease-display cell-to-cell transmission. α-synuclein aggregation is hypothesised to start in autonomic nerve terminals years before the appearance of motor symptoms, and subsequently spread via autonomic nerves to the spinal cord and brainstem. To assess this hypothesis, we investigated sympathetic, parasympathetic, noradrenergic, and dopaminergic innervation in patients with idiopathic rapid eye movement (REM) sleep behaviour disorder, a prodromal phenotype of Parkinson's disease., Methods: In this prospective, case-control study, we recruited patients with idiopathic REM sleep behaviour disorder, confirmed by polysomnography, without clinical signs of parkinsonism or dementia, via advertisement and through sleep clinics in Denmark. We used 11 C-donepezil PET and CT to assess cholinergic (parasympathetic) gut innervation, 123 I-metaiodobenzylguanidine (MIBG) scintigraphy to measure cardiac sympathetic innervation, neuromelanin-sensitive MRI to measure integrity of pigmented neurons of the locus coeruleus, 11 C-methylreboxetine (MeNER) PET to assess noradrenergic nerve terminals originating in the locus coeruleus, and 18 F-dihydroxyphenylalanine (DOPA) PET to assess nigrostriatal dopamine storage capacity. For each imaging modality, we compared patients with idiopathic REM sleep behaviour disorder with previously published reference data of controls without neurological disorders or cognitive impairment and with symptomatic patients with Parkinson's disease. We assessed imaging data using one-way ANOVA corrected for multiple comparisons., Findings: Between June 3, 2016, and Dec 19, 2017, we recruited 22 consecutive patients with idiopathic REM sleep behaviour disorder to the study. Compared with controls, patients with idiopathic REM sleep behaviour disorder had decreased colonic 11 C-donepezil uptake (-0·322, 95% CI -0·112 to -0·531; p=0·0020), 123 I-MIBG heart:mediastinum ratio (-0·508, -0·353 to -0·664; p<0·0001), neuromelanin-sensitive MRI locus coeruleus:pons ratio (-0·059, -0·019 to -0·099; p=0·0028), and putaminal 18 F-DOPA uptake (Ki; -0·0023, -0·0009 to -0·0037; p=0·0013). No between-group differences were detected between idiopathic REM sleep behaviour disorder and Parkinson's disease groups with respect to 11 C-donepezil (p=0·39), 123 I-MIBG (p>0·99), neuromelanin-sensitive MRI (p=0·96), and 11 C-MeNER (p=0·56). By contrast, 15 (71%) of 21 patients with idiopathic REM sleep behaviour disorder had 18 F-DOPA Ki values within normal limits, whereas all patients with Parkinson's disease had significantly decreased 18 F-DOPA Ki values when compared with patients with idiopathic REM sleep behaviour disorder (p<0·0001)., Interpretation: Patients with idiopathic REM sleep behaviour disorder had fully developed pathology in the peripheral autonomic nervous system and the locus coeruleus, equal to that in diagnosed Parkinson's disease. These patients also showed noradrenergic thalamic denervation, but most had normal putaminal dopaminergic storage capacity. This caudorostral gradient of dysfunction supports the hypothesis that α-synuclein pathology in Parkinson's disease initially targets peripheral autonomic nerves and then spreads rostrally to the brainstem., Funding: Lundbeck Foundation, Jascha Foundation, and the Swiss National Foundation., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Objectives: Neuromyelitis optica (NMO)/NMO spectrum disorder (NMOSD) may be misdiagnosed as multiple sclerosis. The aim of this study was to (i) to measure AQP4-IgG in patients who fulfilled the clinical and radiological criteria of NMOSD in the Central Denmark Region and (ii) to estimate the incidence of NMOSD in the region, according to both the 2006 Wingerchuk criteria and the 2015 International Panel for NMO Diagnosis criteria., Materials and Methods: Medical records of all patients diagnosed with a demyelinating disorder in the region from 1 January 2012 to 31 December 2013 were reviewed. Patients were classified as having (i) "NMO" if the 2006 criteria were met, (ii) "NMOSD with AQP4-IgG" or (iii) "NMOSD without/unknown AQP-IgG" if the new 2015 NMOSD criteria were met. Patients with core symptoms were invited to provide a blood sample for AQP4-IgG analysis with an enzyme-linked immunosorbent assay and a cell-based indirect immunofluorescence assay., Results: In 191 patients with core symptoms, one met the 2015 NMOSD with AQP4-IgG criteria. Two patients met the 2006 NMO and 2015 NMOSD without/unknown AQP4-IgG criteria. Among 108 patients providing a blood sample, all were seronegative. The estimated incidence of NMO (2006 criteria) and NMOSD (2015 criteria) was 0.08 and 0.12 per 100 000 person-years, respectively., Conclusion: NMO/NMOSD is a rare disease in the Central Denmark Region, with a considerably lower incidence rate than previously estimated in a neighbouring region., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Idiopathic REM sleep behaviour disorder (iRBD) has been recognised as a significant biomarker for developing a neurodegenerative alpha-synucleinopathy, which is why iRBD is considered to be a prodromal state for alpha-synucleinopathies including Parkinson's disease (PD). Many patients with PD suffer from complaints of pain and present impaired somatosensory function. We hypothesized that pain perception and somatosensory function could be altered already in a preclinical stage of PD including iRBD. Hence, the objective of this study was to investigate pain perception and somatosensory function in patients with iRBD., Methods: Quantitative sensory testing (QST), laser evoked potentials (LEPs), and conditioned pain modulation (CPM) testing were performed in 13 iRBD patients without any clinical signs of PD or narcolepsy (11 males, 2 females, mean age 65.2 years) and 15 gender- and age-matched healthy control subjects (12 males, 3 females, mean age 65.8 years)., Results: Thermal detection thresholds were higher in the iRBD group compared with the control group (cold detection threshold (CDT) p = 0.020, thermal sensory limen (TSL) p = 0.001), indicating an impaired temperature sensation in iRBD patients. The N2/P2 LEPs amplitude was smaller in iRBD patients than controls, but not statistically significant (p = 0.053)., Conclusions: This study found an impaired somatosensory function in iRBD patients, suggesting that somatosensory impairment might be an early feature in the neurodegenerative process of PD., (Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Findings from longitudinal follow-up studies in patients with idiopathic rapid-eye-movement sleep behaviour disorder (IRBD) have shown that most patients will eventually develop the synucleinopathies Parkinson's disease, dementia with Lewy bodies, or multiple system atrophy. Neuroinflammation in the form of microglial activation is present in synucleinopathies and is a potential therapeutic target to halt or delay the neurodegenerative process. We aimed to investigate whether neuroinflammation is present in patients with IRBD and its possible relation to nigrostriatal dopamine function., Methods: In this prospective, case-control, PET study, patients with IRBD and no clinical evidence of parkinsonism and cognitive impairment were recruited from tertiary sleep centres in Spain (Barcelona) and Denmark (Aarhus). We included patients with polysomnography-confirmed IRBD according to established criteria. Healthy controls were recruited through newspaper advertisements. Controls had no motor or cognitive complaints, a normal neurological examination, and a mean group age similar to the IRBD group. In patients with IRBD, we assessed microglial activation in the substantia nigra, putamen, and caudate with 11 C-PK11195 PET, and dopaminergic axon terminal function in the putamen and caudate with 18 F-DOPA PET. Controls underwent either 11 C-PK11195 PET or 18 F-DOPA PET. We compared 18 F-DOPA uptake and 11 C-PK11195 binding potential between groups with an unpaired, two-tailed Student's t test., Findings: Between March 23, 2015, and Oct 19, 2016, we recruited 20 consecutive patients with IRBD and 19 healthy controls. 11 C-PK11195 binding was increased on the left side of the substantia nigra in patients with IRBD compared with controls (Student's t test, mean difference 0·153 [95% CI 0·055 to 0·250], p=0·003), but not on the right side (0·121 [-0·007 to 0·250], p=0·064). 11 C-PK11195 binding was not significantly increased in the putamen and caudate of patients with IRBD. 18 F-DOPA uptake was reduced in IRBD in the left putamen (-0·0032 [-0·0044 to -0·0021], p<0·0001) and right putamen (-0·0032 [-0·0044 to -0·0020], p<0·0001), but not in the caudate., Interpretation: In patients with IRBD, increased microglial activation was detected by PET in the substantia nigra along with reduced dopaminergic function in the putamen. Further studies, including more participants than were in this study and longitudinal follow-up, are needed to support our findings and evaluate whether the presence of activated microglia in patients with IRBD represents a marker of short-term conversion to a clinically defined synucleinopathy in the near future., Funding: Danish Council for Independent Research, Instituto de Salud Carlos III (Spain)., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: Central pain (CP) is a common symptom in MS. Multiple theories are present about the mechanism of CP. Previous studies suggested that lesion of the spinothalamic tract is a necessary condition for development of CP. No previous study has in detail evaluated the association between the specific site of demyelinations and the presence of CP in MS., Objective: The study aimed to evaluate the location of plaques in MS patients with CP including a group of MS patients without pain as a reference group., Methods: All patients underwent a bedside sensory examination and MRI of the brain and spinal cord. MR imaging was acquired on an 1.5 Tesla MR equipment. A trained neuroradiologist, blinded to pain status, evaluated the MRI., Results: Thirteen MS patients with CP and 10 MS patients without pain were included. Allodynia and/or dysesthesia were more frequent in pain patients (11/13 vs. 1/10, P<0.01). No difference was found in the number of patients with plaques in spinothalamic tract, dorsal column-medial lemniscus, dorsolateral funiculus, grey substance, thalamus or capsula interna. A non-significantly lower number of pain patients had lesions in thalamo-cortical pathways (8/13 vs. 10/10, P=0.027)., Conclusions: No association between CP and site of demyelinations was found, although a trend toward a higher prevalence of intact thalamo-cortical pathways was seen in pain patients. CP was associated with allodynia, suggesting central hyperexcitability., (Copyright © 2010 European Federation of International Association for the Study of Pain Chapters. Published by Elsevier Ltd. All rights reserved.)

In essential hypertension (ESS) whole body and vascular nitric oxide (NO) synthesis is generally thought to be reduced. We therefore investigated the systemic and renal responses to acute treatment with N(G)-monomethyl-l-arginine (L-NMMA), a competitive NOS-inhibitor, in 12 patients with ESS and 18 healthy controls (CON) in a randomized, placebo-controlled study. Main effect parameters were renal hemodynamics (glomerular filtration rate [GFR] and renal plasma flow [RPF]), systemic blood pressure (BP), and fractional excretions of sodium (FE(Na)) and lithium (FE(Li)). Experiments were performed on two occasions for each subject studying the effects of either L-NMMA (3 mg/kg intravenously) or placebo. The patients with ESS were studied after at least 14 days off antihypertensive medication. Renal hemodynamics were assessed by the clearances of (125)I-hippuran (RPF) and (51)Cr-EDTA (GFR). The L-NMMA induced a significant increase in systemic BP and significant reductions in RPF, FE(Na), and FE(Li) in both groups. The increase in diastolic BP was significantly attenuated in ESS (ESS: 8% +/- 2% v CON: 14% +/- 2%, P < .05). The GFR and RPF were equally reduced by L-NMMA in both groups (RPF(ESS): -19% +/- 4% v RPF(CON): -15% +/- 3%, P = not significant [NS]). However, the reduction in FE(Na) was enhanced in ESS (ESS: -42% +/- 7% v CON: -25% +/- 3%, P < .01). The FE(Li) decreased equally in both groups (ESS: -17% +/- 2% v CON: -17% +/- 6%, P = NS). It is concluded that acute NO blockade in ESS is accompanied by a reduced systemic pressor response, an unchanged renal hemodynamic response, and an enhanced reduction in FE(Na). The results suggest that patients with essential hypertension are highly dependent on NO to maintain sodium excretion.

Cannabinoids reduce allodynia/hyperalgesia in animal pain models, but few clinical studies evaluated the analgesic action in humans. We aimed to evaluate the effect of delta-9-tetrahydrocannabinol (dronabinol) on central pain in MS patients. Twenty-four MS patients participated in a double-blind placebo-controlled crossover trial. Dronabinol reduced the spontaneous pain intensity significantly compared with placebo (4.0 (2.3-6.0) vs. 5.0 (4.0-6.4), median (25th-75th percentiles), p = 0.02). Though dronabinol's analgesic effect is modest, its use should be evaluated considering the general difficulty in treating central pain.

Breakthrough pain or transient worsening of pain in patients with an ongoing steady pain is a well known feature in cancer pain patients, but it is also seen in non-malignant pain conditions with involvement of nerves, muscles, bones or viscera. Continuous and intermittent pain seems to be a general feature of these different pain conditions, and this raises the possibility of one or several common mechanisms underlying breakthrough pain in malignant and non-malignant disorders. Although the mechanisms of spontaneous ongoing pain and intermittent flares of pain (BTP) may be difficult to separate, we suggest that peripheral and/or central sensitization (hyperexcitability) may play a major role in many causes of BTP. Mechanical stimuli (e.g. micro-fractures) changes in chemical environments and release of tumour growth factors may initiate sensitization both peripherally and centrally. It is suggested that sensitization could be the common denominator of BTP in malignant and non-malignant pain.

Central neuropathic pain is well known in multiple sclerosis (MS), but the underlying mechanisms are unclear. In the present study we studied sensory function in MS patients with pain, MS patients without pain and healthy subjects in order to clarify the role of sensory abnormalities in pain. Fifty MS patients with pain were randomly recruited from a previous epidemiological MS study in Aarhus County, Denmark. Age and gender stratified MS patients without pain (N=50) and healthy subjects (N=50) served as controls. Patients with pain underwent a structured pain interview. Sensory function was examined by bedside and quantitative sensory testing. Quality of life was assessed using the health-related quality of life questionnaire, SF-36. Patients with pain had lower pressure pain threshold than pain-free patients (260 kPa vs. 322 (median), P=0.02) otherwise quantitative sensory testing was similar. Pain patients more frequently had cold allodynia (9/50 vs. 0/50, P=0.003) and abnormal temporal summation (10/48 vs. 3/49, P=0.03). Fifty-eight percent had central pain. Central pain patients did not differ from musculoskeletal pain patients in quantitative sensory testing, but allodynia was more common in MS patients with central pain. Pain patients scored lower in all dimensions of SF-36 compared with pain-free patients and healthy subjects. The results suggest that pain in MS is central in more than half of the patients and is associated with mechanical or thermal hyperalgesia.

Objective: To evaluate the effect of methotrexate (MTX) and other disease-modifying anti-rheumatic drugs (DMARDs) alone or in combination with non-steroidal anti-inflammatory drugs (NSAIDs) on the urinary excretion of alpha-glutathione S-transferase (alpha-GST) and albumin in rheumatoid arthritis (RA) patients., Methods: Nineteen RA patients starting treatment with MTX were followed for 1 year with measurements of urinary alpha-GST, urinary albumin, and urinary and plasma creatinine at the start of treatment, and after 16, 28, and 52 weeks. A larger group of RA patients (n = 72) undergoing long-term treatment with different DMARDs was compared with 79 healthy controls regarding urinary alpha-GST and albumin. alpha-GST was quantified by an enzyme immunoassay. Urine albumin was measured turbidimetrically., Results: The urine-alpha-GST/urine-creatinine ratio and the urine-albumin/urine-creatinine ratio did not change during 52 weeks of treatment with MTX. The long-term DMARD-treated RA patients and the healthy controls were comparable with regard to the urine-alpha-GST/urine-creatinine ratio and the urine-albumin/urine-creatinine ratio. All patients had preserved renal function as assessed by plasma creatinine, and none had proteinuria using urine dipstick methods., Conclusion: DMARD-treated RA patients with normal serum creatinine had no detectable renal injuries assessed by the urinary excretions of alpha-GST and albumin.

Objective: To evaluate the effect of the oral synthetic delta-9-tetrahydrocannabinol dronabinol on central neuropathic pain in patients with multiple sclerosis., Design: Randomised double blind placebo controlled crossover trial., Setting: Outpatient clinic, University Hospital of Aarhus, Denmark., Participants: 24 patients aged between 23 and 55 years with multiple sclerosis and central pain., Intervention: Orally administered dronabinol at a maximum dose of 10 mg daily or corresponding placebo for three weeks (15-21 days), separated by a three week washout period., Main Outcome Measure: Median spontaneous pain intensity (numerical rating scale) in the last week of treatment., Results: Median spontaneous pain intensity was significantly lower during dronabinol treatment than during placebo treatment (4.0 (25th to 75th centiles 2.3 to 6.0) v 5.0 (4.0 to 6.4), P = 0.02), and median pain relief score (numerical rating scale) was higher (3.0 (0 to 6.7) v> 0 (0 to 2.3), P = 0.035). The number needed to treat for 50% pain relief was 3.5 (95% confidence interval 1.9 to 24.8). On the SF-36 quality of life scale, the two items bodily pain and mental health indicated benefits from active treatment compared with placebo. The number of patients with adverse events was higher during active treatment, especially in the first week of treatment. The functional ability of the multiple sclerosis patients did not change., Conclusions: Dronabinol has a modest but clinically relevant analgesic effect on central pain in patients with multiple sclerosis. Adverse events, including dizziness, were more frequent with dronabinol than with placebo during the first week of treatment.

Background: Pain is an important symptom in patients with multiple sclerosis (MS). The estimated pain prevalence varies between 30% and 90%. To our knowledge, previous studies do not include a whole population sample of patients with MS., Objective: To assess pain prevalence and its clinical characteristics and impact on daily life in a population sample of MS patients and in a reference group., Design: Postal survey., Setting: Aarhus County, Denmark., Participants: The population of patients with definite MS in Aarhus County (n = 771) and a sex- and age-stratified reference group from the general population (n = 769)., Main Outcome Measures: Pain prevalence, intensity, and treatment requirement; and the impact of pain on daily life., Results: Response rates for MS patients and reference subjects were 81.3% and 63.3%, respectively. Pain in the month preceding assessment occurred in 79.4% of MS patients and in 74.7% of reference subjects (prevalence proportion ratio, 1.06; 95% confidence interval, 0.99-1.13). Patients with MS had a higher pain intensity ("when pain is at its least" median visual analog scale score, 20.0 vs 11.0 mm [P<.01];and "when pain is at its worst" median visual analog scale score, 68.0 vs 55.0 mm [P<.01]). Daily intake of analgesics occurred in 24.4% of MS patients and 9.0% of reference subjects (prevalence proportion ratio, 2.7; 95% confidence interval, 2.0-3.6). Patients with MS more often reported that pain interfered with daily life "most of the time" or "all the time.", Conclusions: The frequency of reported pain in MS patients was not higher than in the background population. However, pain intensity, the need for analgesic treatment, and the impact of pain on daily life were higher in MS patients.

Background: Non-steroidal anti-inflammatory drugs (NSAIDs) are known to be potentially nephrotoxic agents. NSAIDs inhibit the enzyme cyclo-oxygenase and thereby block the prostaglandin synthesis in the kidneys. Cyclo-oxygenase exists in two isoforms (COX-1 and COX-2). It has been proposed that NSAIDs with preferential COX-2 selectivity have fewer renal side effects than drugs with preferential COX-1 selectivity. Etodolac is a relative selective inhibitor of COX-2, while ibuprofen has a higher potency against COX-1 than COX-2., Objective: In this study, we compared the effects of etodolac and ibuprofen on renal function, plasma renin, plasma arginine vasopressin and the urinary excretion of albumin and alpha-glutathione-S-transferase (alpha-GST)., Methods: In a randomised, double-blind, three-way crossover study with placebo, we compared the effects of 2 weeks of treatment with ibuprofen and etodolac on renal haemodynamics [glomerular filtration rate (GFR), renal plasma flow (RPF) and filtration fraction (FF)], tubular function and plasma concentrations of the hormones renin (PRC) and arginine vasopressin (AVP) in 18 healthy subjects. In addition, we examined the effects on the urinary excretion of albumin and alpha-GST as markers of renal injury., Results: No differences were found between the three treatments, placebo, ibuprofen and etodolac, in the effects on GFR, RPF, FF, free water clearance, urinary output or fractional excretion of potassium and sodium. However, ibuprofen, in contrast to etodolac, caused a significant decrease in both lithium clearance (-16% versus placebo) and the fractional excretion of lithium (-17% versus placebo), suggesting an increase in the reabsorption in the proximal tubuli. PRC was reduced significantly by ibuprofen (-32% versus placebo) but not etodolac. None of the drugs changed AVP. Fourteen days of treatment with ibuprofen caused a significant decrease (-47% versus placebo) in the urinary excretion of alpha-GST, while no changes were seen after etodolac. None of the drugs changed the urinary excretion of albumin., Conclusion: In conclusion, a 14-day administration of etodolac or ibuprofen in therapeutic doses did not affect the renal haemodynamics, the net excretion of electrolytes or the urinary excretion of albumin in healthy subjects. However, ibuprofen, in contrast to etodolac, caused a reduction in PRC, suggesting that COX-1 is involved in basal renin release in humans. Furthermore, ibuprofen decreased lithium excretion suggesting that COX-1 is involved in the re-absorption of sodium and/or water in the proximal tubuli. The reduction in the urinary excretion of alpha-GST by ibuprofen may be caused by an inhibition of the detoxification enzyme by ibuprofen. Overall the study indicates that only small differences in the effects of the two drugs on renal function in healthy subjects exist during a treatment period of 2 weeks.