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The major characteristics of Alzheimer's disease (AD) are amyloid plaques, consisting of aggregated beta amyloid (A beta) peptides, together with tau pathology (tangles, neuropil treads and dystrophic neurites surrounding the plaques), in the brain. Down's syndrome (DS) individuals are at increased risk to develop AD-type pathology; most DS individuals have developed substantial pathology already at the age of 40. DS individuals have an extra copy of chromosome 21, harbouring the amyloid precursor protein gene (APP). Our aim was to investigate the A beta peptide pattern in DS and AD brains to investigate differences in their amyloid deposition and aggregation, respectively. Cortical tissue from patients with DS (with amyloid pathology), sporadic AD and controls were homogenized and fractionated into TBS (water soluble) and formic acid (water insoluble) fractions. Immunoprecipitation (IP) was performed using a variety of antibodies targeting different A beta species including oligomeric A beta. Mass spectrometry was then used to evaluate the presence of A beta species in the different patient groups. A large number of A beta peptides were identified including A beta 1-X, 2-X, 3-X, 4-X, 5-X, 11-X, and A beta peptides extended N terminally of the BACE1 cleavage site and ending at amino 15 in the A beta sequence APP/A beta(-X to 15), as well as peptides post-translationally modified by pyroglutamate formation. Most A beta peptides had higher abundance in AD and DS compared to controls, except the APP/A beta(-X to 15) peptides which were most abundant in DS followed by controls and AD. Furthermore, the abundancies of A?X-40 and A beta X-34 were increased in DS compared with AD. A beta 1-40, A beta 1-42, and A beta 4-42 were identified as the main constitutes of protofibrils (IP'd using mAb158) and higher relative A beta 1-42 signals were obtained compared with samples IP'd with 6E10 + 4G8, indicating that the protofibrils/oligomers were enriched with peptides ending at amino acid 42. All A? peptides found in AD were also present in DS indicating similar pathways of A beta peptide production, degradation and accumulation, except for APP/A beta(-X to 15). Likewise, the A beta peptides forming protofibrils/oligomers in both AD and DS were similar, implying the possibility that treatment with clinical benefit in sporadic AD might also be beneficial for subjects with DS.

Down syndrome (DS) is caused by trisomy of chromosome 21, which leads to a propensity to develop amyloid β (Aβ) brain pathology in early adulthood followed later by cognitive and behavioral deterioration. Characterization of the Aβ pathology is important to better understand the clinical deterioration of DS individuals and to identify interventive strategies. Brain samples from people with DS and Alzheimer's disease (AD), as well as non-demented controls (NDC), were analyzed with respect to different Aβ species. Immunohistochemical staining using antibodies towards Aβ was also performed. Elevated levels of soluble Aβ protofibrils and insoluble Aβx-40 and Aβx-42 in formic acid brain extracts, and elevated immunohistochemical staining of Aβ deposits were demonstrated with the antibody BAN2401 (lecanemab) in DS and AD compared with NDC. These data and the promising data in a large phase 2 CE clinical trial with lecanemab suggest that lecanemab may have the potential to preserve cognitive capacity in DS. Lecanemab is currently in a phase 3 CE clinical trial.

There has been a series of high-profile failures of drugs in clinical trials of acute ischaemic stroke that were designed to meet criteria necessary for drug regulatory approval. This has, again, called into question the value of animal models for identifying effective neuroprotective agents. Here, we review evidence that physiological changes (reperfusion, hyperglycaemia, hypothermia and blood pressure) produce comparable changes in outcome in both animal models and human stroke patients, which indicates that the models should identify clinically effective neuroprotective agents. We suggest that most clinical failures have occurred because compounds were administered differently in animal and clinical studies. We review earlier guidelines on the information that is necessary from preclinical studies before a compound enters clinical trials, and propose modifications to these guidelines.

Aims This analysis was performed to investigate the population pharmacokinetics of clomethiazole and its effect on the natural course of sedation in acute stroke patients using a nonlinear mixed effects modelling approach. Methods One thousand five hundred and forty-six acute stroke patients (774 on active treatment) from 166 centres were included in three randomized, double-blind, placebo-controlled phase III efficacy and safety studies. A total dose of 68 mg kg−1 clomethiazole edisilate was given as a three-phase i.v.-infusion over 24 h. Three blood samples were drawn from all patients to characterize the pharmacokinetics. Sedation was monitored throughout the entire treatment period and the degree of sedation was measured on a discrete ordinal scale with six levels. Models were fitted to the data using the software NONMEM. Results Clomethiazole was characterized by a two-compartment pharmacokinetic model with interindividual variability in all structural parameters. For a patient weighing 75 kg, the average CL, V1, Q, and V2 was estimated to be 52.7 l h−1, 82.5 l, 167 l h−1 and 335 l, respectively. The interindividual variability in CL, V1, Q and V2 was estimated to be 48%, 53%, 42% and 54%, respectively. Increasing body weight and concomitant administration of liver enzyme inducing drugs were found to increase clearance (by 0.5 l h−1 kg−1 and 40%, respectively). Increasing weight also increased the volume of distribution (1.1 l kg−1 for V1 and 4.7 l kg−1 for V2). A six-category proportional odds model with a component including the natural course of sedation following placebo administration, a drug component (present or absent) and an interindividual variability component described the degree of sedation. Stroke severity as measured on the NIH-stroke scale on admission and drug treatment were the most important predictors of sedation, but a nonlinear increase in sedation with increasing age was also found. Increasing body weight increased the sedative drug effect. Conclusions The pharmacokinetics of clomethiazole were characterized in acute stroke patients and the analysis excluded several possible covariates of interest in drug development. The time course of sedation could be quantitatively described during the first 24 h following an acute stroke in the presence or absence of clomethiazole treatment.

Background: Previous reports have suggested left hemispheric dominance for maintaining consciousness, although there is controversy over this claim. Objective: To compare early impairment of level of consciousness between patients with right and left hemispheric stroke. Methods: Data from 564 patients with ischaemic stroke enrolled in the placebo arm of a trial of a putative neuroprotectant were analysed. All patients had major hemispheric stroke with cortical dysfunction, visual field deficit, and limb weakness, with symptom onset within 12 hours of enrolment. Patients were prospectively evaluated on a predefined scale (1–6; 1 = fully awake, higher scores representing greater impairment) to measure level of consciousness at multiple time points over the initial 24 hours after presentation. The National Institutes of Health (NIH) stroke scale score at presentation and infarct volume at 30 days were determined. Results: Some degree of impairment in level of consciousness was observed in 409 of the 564 patients (73%). Median maximum sedation score was 2 for both right and left hemispheric stroke (p = 0.91). Mean sedation score over 24 hours was 1.5 for both right and left stroke (p = 0.75). There was no difference between level of consciousness scores in right and left stroke at any individual time point during the 24 hour monitoring period. No association between side and impairment in level of consciousness was seen after adjustment for stroke severity and infarct volume. Conclusions: In contrast to previous reports, there was no evidence for hemispheric dominance for consciousness in the setting of a major hemispheric stroke.

Clomethiazole is virtually completely eliminated by hepatic metabolism. This study was designed to assess the impact of liver impairment on its elimination and sedative effects.Eight patients with mild liver impairment (Child-Pugh grade A), eight patients with moderate/severe liver impairment (Child-Pugh grade B/C) and eight healthy subjects of similar age were given 68 mg/kg clomethiazole edisilate according to a 24-h infusion scheme aimed at producing minimum sedation as it was intended for clinical use in patients with stroke. Concentrations of clomethiazole and its active alpha-carbon hydroxylated metabolite NLA-715 were followed in plasma and urine for 96 h and 24 h, respectively. Sedation was monitored using a scale from 1 to 6.The fraction excreted unchanged in urine was less than 0.2% for clomethiazole and less than 0.4% for NLA-715. Urine concentrations of clomethiazole were strongly correlated (r(2)=0.60) to plasma concentrations and approximately equal to unbound plasma concentrations. Plasma levels of NLA-715 increased steadily during the infusion, eventually reaching mean levels exceeding those of clomethiazole in all groups. Plasma clearance of clomethiazole in subjects with mildly impaired liver function was not statistically different from that of healthy controls (40 l/h vs 44 l/h). In subjects with moderate/severe liver impairment, there was a 50% reduction in clearance. Sedation was not observed except in two subjects in the Child-Pugh A group showing mild sedation.The reduced clomethiazole clearance in patients with moderate/severe liver impairment seems to call for a reduction of clomethiazole dosage. However, sedation was not observed in this group at the investigated dose level.

Background and Purpose— NXY-059 is a nitrone-based free radical–trapping agent in development for acute stroke. In patients with acute stroke, NXY-059 is well tolerated at concentrations known to be associated with neuroprotection in animal models of transient cerebral ischemia; however, higher target concentrations appear necessary on the basis of animal models of permanent ischemia. Methods— This was a randomized, double-blind, placebo-controlled, parallel-group, dose-escalation, multicenter study that evaluated safety, tolerability, and plasma concentrations of 2 NXY-059 dosing regimens within 24 hours of acute stroke. NXY-059 was administered as either 915 mg over 1 hour followed by 420 mg/h for 71 hours or 1820 mg for 1 hour followed by 844 mg/h for 71 hours; plasma concentrations were monitored. Neurological and functional outcomes were recorded for up to 30 days. Results— One hundred thirty-five patients were recruited, of whom 134 received study treatment and completed assessments (844 mg/h, n=39; 420 mg/h, n=48; placebo, n=47). Mean age was 69 years (range, 34 to 92 years), and baseline National Institutes of Health Stroke Scale score was 8.5 (SD, 6.6). Serious adverse events occurred in 3, 17, and 13 patients, respectively, with deaths in 0, 4, and 3 patients and treatment discontinuations because of adverse events in 0, 1, and 3 patients. Good outcome, defined by modified Rankin Scale score of 0 or 1, was seen in 53%, 29% and 40%, respectively. No safety concern was identified in analysis of body temperature, blood pressure, or other laboratory parameters. The unbound plasma concentration at steady state was 260±79 μmol/L, exceeding the target of 200 μmol/L in the high-dose group. Conclusions— NXY-059 was well tolerated in patients with an acute stroke at and above concentrations shown to be neuroprotective in an animal model when initiated 4 hours after onset of permanent focal ischemia.

Objective. NXY-059 is a nitrone-based, free-radical trapping agent being developed for the treatment of acute ischaemic stroke. Elimination of NXY-059 is primarily renal. The objective of the study was to investigate the pharmacokinetics of NXY-059 in subjects with renal impairment. Methods. Twenty-four subjects with a glomerular filtration rate (GFR) ranging from 19 ml/min to 100 ml/min received NXY-059 intravenously over a 24-h period. Drug in plasma and urine was measured for 72 h. One-hour loading infusion rates were proportional to body weight, while maintenance infusion rates were proportional to GFR. Target plasma levels were 60 µmol/l for subjects with mild (GFR 50–100 ml/min) and moderate (GFR 30–49 ml/min) renal impairment, and 30 µmol/l for subjects with severe renal impairment (GFR

Background and Purpose —Increased free radical formation contributes to the damage caused to the brain by acute ischemia. NXY-059 is a nitrone-based free radical trapping agent in development for acute stroke. NXY-059 has neuroprotective efficacy when given 5 hours after onset of transient focal ischemia in the rat. Methods —This was a randomized, double-blind, placebo-controlled, parallel group, multicenter study that evaluated the safety and tolerability of 2 NXY-059 dosing regimens compared with placebo within 24 hours of acute stroke. NXY-059 was administered as either 250 mg over 1 hour followed by 85 mg/h for 71 hours or 500 mg over 1 hour followed by 170 mg/h for 71 hours; plasma concentrations were monitored. Neurological and functional outcomes were recorded up to 30 days. Results —One hundred fifty patients were recruited, of whom 147 received study treatments and completed assessments (50 placebo, 48 lower-dose NXY-059, 49 higher-dose NXY-059). Mean (±SD) age was 68 (±10) years, and baseline National Institutes of Health Stroke Scale score was 7.9 (±6.2). Serious adverse events occurred in 16%, 23%, and 16% of patients, respectively, with deaths in 0%, 10%, and 4%, largely following the proportions with primary intracerebral hemorrhage (6%, 16%, and 8%). Hyperglycemia, headache, and fever were common but not related to treatment. The mean unbound steady state NXY-059 plasma concentrations were 25 and 45 μmol/L, respectively. Population pharmacokinetic analysis estimated clearance to be 4.6 L/h. Conclusions —NXY-059 was well tolerated in patients with an acute stroke. The testing of higher doses in future trials may be justified.

Background and Purpose: Clomethiazole (CMZ) is a neuroprotectant that may improve outcome in patients with acute major strokes. In a previous study that included 94 hemorrhagic stroke patients (CLASS), a mortality reduction and functional outcome favorable to CMZ was seen. We sought to establish the safety of CMZ in acute hemorrhagic stroke patients and to determine whether a trial of medical therapy for cerebral hemorrhage was feasible. Methods: The safety of CMZ (n = 96) versus a placebo (n = 102) in hemorrhagic stroke patients was evaluated in a randomized, double-blind trial. Treatment began after a computed tomography (CT) scan confirmed the presence of hemorrhage and within 12 hours from symptom onset. Patients received 68 mg/kg of CMZ intravenously over 24 hours. Safety was assessed by collecting serious adverse events (SAE), including deaths up to 90 days after treatment. Functional and neurologic outcome were also monitored. Results: Hemorrhage volumes were found to be similar between groups (26 ± 56 mL CMZ v 26 ± 35 mL placebo). Sedation was reported as an adverse event during therapy in 55% of the CMZ patients versus 13% of the placebo patients. The number of SAE reports was 53 in the CMZ group and 46 in the placebo group. Differences on functional outcome measures were minor. Death within 90 days occurred in 19 CMZ patients versus 11 placebo patients (Odds Ratio [OR] 2.04; 95% confidence interval [CI] 0.92, 4.55; P = .08). After adjusting for baseline covariate imbalances, the mortality difference was less apparent (OR 1.82; 95% CI 0.69, 4.81; P = .23). Conclusions: The feasibility of performing neuroprotectant trials for acute cerebral hemorrhage patients has been established, but requires careful balancing of important predictive indicators, including baseline severity, hematoma location, presence of intraventricular blood, and possibly, coumadin use. The clinical experience to date has identified no specific major safety concerns with the use of CMZ in acute hemorrhagic stroke patients. Additional clinical trials will be required to confirm safety and establish the efficacy of CMZ in acute hemorrhagic stroke patients.

Clomethiazole is a drug with sedative properties effective in laboratory studies of brain ischemia. A large European multicenter trial of clomethiazole in acute stroke patients showed no benefit overall, but subgroup analysis indicated that patients with large infarctions may have benefited from treatment. To confirm this preliminary finding, we have designed CLASS-IHT, the Clomethiazole for Acute Stroke Study in Ischemic, Hemorrhagic and TPA Treated Patients, to be conducted in North America. Patients who suffer large cerebral infarctions and present within 12 hours of symptom onset are eligible. Patients will be randomized to receive clomethiazole 68 mg/kg over 24 hours or vehicle, using a dosing scheme based on the pharmacokinetics measured in the first trial. Outcome assessments include stroke scales, the Barthel Index, and lesion volume. An additional study of health economic outcomes is planned. The primary endpoint for CLASS-I will be the Barthel Index 90 days after stroke. A total of 1,200 patients will be randomized to CLASS-I, and in safety-only trials, 200 patients with cerebral hemorrhage will be randomized into CLASS-H and another 100 to 200 patients will be randomized into CLASS-T. The details of the protocols for all three studies are presented.

The pattern of brain perfusion of four patients with writer's cramp and four control subjects were examined using positron emission tomography scans after [(15)O] butanol injections. Each subject was scanned 12 times to cover three repetitions of four different motor tasks with the right hand. Drawing of horizontal lines and variable durations of the writing of a prelearned text were performed in a pseudorandom order, the latter task commencing either simultaneously with or 30 sec or 120 sec before the tracer injection. The perceived difficulty and signs of dystonia progressed in correlation to the duration of writing. Statistical parametric maps were calculated to test hypotheses of regional specific effects dependent on the performed motor tasks. The patients with writer's cramp had progressively increased activity in the left primary sensorimotor and premotor cortices, the left thalamus, and the cerebellum with a right-side predominance in correlation to the duration of writing. The regions with activity increases thus corresponded to a cerebrocerebellar motor circuit. The duration of writing correlated to a progressive reduction of activity in the patients' left supramarginal and angular gyri (Brodmann areas 40 and 39) and an inferior part of the left temporal lobe (area 20). The control subjects had neither a significant increase or decrease of activity in correlation to the duration of writing. Group-specific differences were confirmed statistically in split-plot interaction analyses.

Response It is premature to comment on SAINT II before any manuscript is published. However, the suggestion that different products were used for the 2 SAINT trials can be discounted. Relevant knowledge contained in the patent application was applied identically to …

NXY-059 (disufenton sodium, Cerovive, a nitrone with neuroprotective and free radical trapping properties (in experimental stroke) is under development for the treatment of acute stroke. The objectives of this study were to develop a population pharmacokinetic model for NXY-059 in acute stroke patients and to estimate individualised dosing strategies for NXY-059 using preclinical pharmacological and clinical pharmacokinetic information and knowledge of characteristics of the patient population.NXY-059 was given as a continuous intravenous infusion for 72 hours, including a 1-hour loading infusion. Maintenance infusion rates were individualised based on creatinine clearance (CL(CR)). Population pharmacokinetic models were derived using NONMEM software. Optimal dosing strategies, individualised based on CL(CR) or bodyweight, were estimated using the population pharmacokinetic models, empirical covariate distributions relevant for the target population, and a target definition. Dosing strategies were selected based on target fulfillment criteria and parsimony.Pharmacokinetic data from 179 patients with acute ischaemic or haemorrhagic stroke, included in two clinical studies, were used for the analyses. Patients were aged 34-92 years with varying degrees of renal impairment (estimated CL(CR) 20-143 mL/min).The final population model based on data from both studies comprised a two-compartment model with unexplained interpatient variability for clearance (23% coefficient of variation [CV]) and central volume of distribution (40% CV). Part of the variability in clearance and volume of distribution was explained by CL(CR) and bodyweight, respectively. Typical clearance was estimated to 4.54 L/h in a patient with CL(CR) of 70 mL/min. The preferred dosing strategy for NXY-059 comprised an initial loading infusion (the same for all patients) followed by an individualised maintenance infusion on the basis of CL(CR) (three dosing categories) with cut-off values (at which infusion rates are incremented or decremented) of 50 and 80 mL/min.The results illustrate how an individualised dosing strategy, given a pharmacokinetic target, for NXY-059 was successfully optimised through estimation using the increasing pharmacokinetic and pharmacodynamic knowledge during a clinical drug development programme. The chosen dosing strategy of NXY-059 provides an easily adapted treatment regimen for acute stroke, resulting in early achievement of target plasma concentrations.

This analysis was performed to investigate the population pharmacokinetics of clomethiazole and its effect on the natural course of sedation in acute stroke patients using a nonlinear mixed effects modelling approach.One thousand five hundred and forty-six acute stroke patients (774 on active treatment) from 166 centres were included in three randomized, double-blind, placebo-controlled phase III efficacy and safety studies. A total dose of 68 mg kg(-1) clomethiazole edisilate was given as a three-phase i.v.-infusion over 24 h. Three blood samples were drawn from all patients to characterize the pharmacokinetics. Sedation was monitored throughout the entire treatment period and the degree of sedation was measured on a discrete ordinal scale with six levels. Models were fitted to the data using the software NONMEM.Clomethiazole was characterized by a two-compartment pharmacokinetic model with interindividual variability in all structural parameters. For a patient weighing 75 kg, the average CL, V1, Q, and V2 was estimated to be 52.7 l h(-1), 82.5 l, 167 l h(-1) and 335 l, respectively. The interindividual variability in CL, V1, Q and V2 was estimated to be 48%, 53%, 42% and 54%, respectively. Increasing body weight and concomitant administration of liver enzyme inducing drugs were found to increase clearance (by 0.5 l h(-1) kg(-1) and 40%, respectively). Increasing weight also increased the volume of distribution (1.1 l kg(-1) for V1 and 4.7 l kg(-1) for V2). A six-category proportional odds model with a component including the natural course of sedation following placebo administration, a drug component (present or absent) and an interindividual variability component described the degree of sedation. Stroke severity as measured on the NIH-stroke scale on admission and drug treatment were the most important predictors of sedation, but a nonlinear increase in sedation with increasing age was also found. Increasing body weight increased the sedative drug effect.The pharmacokinetics of clomethiazole were characterized in acute stroke patients and the analysis excluded several possible covariates of interest in drug development. The time course of sedation could be quantitatively described during the first 24 h following an acute stroke in the presence or absence of clomethiazole treatment.

Background and Purpose — A previous trial (the Clomethiazole Acute Stroke Study) generated the hypothesis that clomethiazole is effective in patients with a major ischemic stroke (total anterior circulation syndrome), and this was tested in the present study. Methods — A total of 1198 patients with major ischemic stroke and a combination of limb weakness, higher cortical dysfunction, and visual field deficits were randomly assigned to clomethiazole (68 mg/kg IV over 24 hours) or placebo. The study drug was initiated within 12 hours of symptom onset. Functional outcome and neurological recovery were assessed at days 7, 30, and 90, with the proportion of patients with a Barthel Index ≥60 at last follow-up as the primary outcome measure. Results — The patients were randomly assigned equally, and the two treatment groups were well matched for baseline characteristics, including stroke severity (mean National Institutes of Health Stroke Scale score 16.9±5.2). Ninety-six percent were classified as total anterior circulation syndrome. The proportion of patients reaching a Barthel Index score of ≥60 was 42% in the clomethiazole-treated group and 46% in the placebo-treated group (odds ratio, 0.81; 95% CI, 0.62 to 1.05; P =0.11). There was no evidence of efficacy on any secondary outcome variables (modified Rankin Score, National Institutes of Health Stroke Scale, Scandinavian Stroke Scale, and 30-day CT infarct volumes) compared with placebo. Subgroup analysis showed a similar lack of treatment effect in patients treated early ( Conclusions — The target population was selected, and sufficient drug was given to produce the expected pharmacological effect in the brain. Clomethiazole does not improve outcome in patients with major ischemic stroke.

Previous electrophysiologic studies on the effects of local injections of botulinum toxin type A (BTX-A) have indicated impaired neuromuscular transmission in distant muscles. To further study possible distant effects of repeated BTX-A injections, we obtained percutaneous muscle biopsies of the vastus lateralis muscle from 11 patients with cervical dystonia. We examined the biopsies with histopathology and morphometry, and compared them with age-matched healthy controls. There was an increased frequency of angular atrophic type IIB fibers in the patient group, and the mean size of IIB fibers was significantly smaller (p0.05). In addition, there was a negative correlation between accumulated dose of botulinum toxin and relative size of type IIA fibers (p0.05). We postulate that the observed atrophy is due to distant effects of botulinum toxin causing progressive denervation-like changes in non-treated muscle. This observation calls for further, prospective studies of the long-term effects of the treatment.