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Zusammenfassung Hintergrund Patienten mit Multipler Sklerose (MS) leiden in 40–70 % der Fälle unter kognitiven Störungen. Der kognitive Status gilt erwiesenermaßen als Prädiktor für Berufsfähigkeit und frühzeitige Berentung. Eine regelmäßige Erfassung der kognitiven Leistungsfähigkeit ist somit dringend indiziert. Zielsetzung Die deutsche Fassung der international empfohlenen BICAMS (Brief International Cognitive Assessment for Multiple Sclerosis) -Batterie wurde auf Praktikabilität in der klinischen Routine neurologischer Praxen in Deutschland multizentrisch überprüft. Material und Methoden Medizinische Fachangestellte (MFAs) wurden hinsichtlich der Durchführung und Auswertung von BICAMS geschult. Alle ausgewerteten Testbögen wurden von unabhängigen neuropsychologischen Experten überprüft. Ergebnisse Insgesamt 1606 BICAMS-Datensätze wurden in 65 Zentren erhoben. Von diesen konnten 1573 analysiert werden. 49,7 % der erhobenen Datensätze wurden inklusive aller Auswerteschritte korrekt durchgeführt. Bei den anderen 50,3 % fanden sich Durchführungs‑, Auswerte- oder Transformationsfehler. Nach Bereinigung der Stichprobe durch fehlerbehaftete Fälle ergaben sich Werte der Interrater-Reliabilität pro Testverfahren in Höhe von ICC $$\geq$$ ≥ 0,953. Diskussion Grundsätzlich ist BICAMS für den Einsatz im klinischen Alltag sehr zu empfehlen. Es bleibt allerdings zu betonen, dass obgleich die Interrater-Reliabilität für die final bereinigte Stichprobe sehr hoch war, im Gesamtdatensatz 50,3 % Durchführungs‑, Auswerte- oder Transformationsfehler gefunden wurden. Daraus lässt sich die Notwendigkeit ableiten, nichtpsychologisches Personal noch eingehender in der Anwendung und Auswertung von BICAMS durch Experten zu schulen und zu supervidieren.

Background: The international standard to screen for cognitive impairment in multiple sclerosis (MS) is BICAMS (Brief International Cognitive Assessment for MS). However, with an application time of approximately 20 minutes, the battery might be too time consuming from a pragmatic perspective of a routine examination. Objectives: To examine the relative sensitivity and specificity of a BICAMS short version and its validity compared to the total battery. Methods: The German BICAMS version was applied comprising the Symbol Digit Modalities Test (SDMT), the Brief Visuospatial Memory Test–Revised (BVMT-R) and the Rey Auditory Verbal Learning Test (RAVLT; German VLMT). Single tests and two-test combinations were compared regarding conformity with the total battery. Results: Examining 1320 MS patients, the two-test combination of SDMT-BVMT-R was the most sensitive (92.7%) to impairment and showed the strongest agreement with the total battery (κ = 0.95). Performing binary logistic regression analyses, this combination was also validated by its association with employment status. Conclusion: Application of the total BICAMS battery should be the goal to strive for. However, in time-restricted clinical settings, the combined application of SDMT and BVMT-R is a recommendable alternative with an application time of 10 minutes, while single tests alone are not sufficiently sensitive.

To evaluate the 5-year real-world benefit-risk profile of fingolimod in patients with relapsing-remitting MS (RRMS) in Germany.Post-Authorization Non-interventional German sAfety study of GilEnyA (PANGAEA) is a non-interventional real-world study to prospectively assess the effectiveness and safety of fingolimod in routine clinical practice in Germany. The follow-up period comprised 5 years. Patients were included if they had been diagnosed with RRMS and had been prescribed fingolimod as part of clinical routine. There were no exclusion criteria except the contraindications for fingolimod as defined in the European label. The effectiveness and safety analysis set comprised 4032 and 4067 RRMS patients, respectively.At the time of the 5-year follow-up of PANGAEA, 66.57% of patients still continued fingolimod therapy. Annualized relapse rates decreased from baseline 1.5 ± 1.15 to 0.42 ± 0.734 at year 1 and 0.21 ± 0.483 at year 5, and the disability status remained stable, as demonstrated by the Expanded Disability Status Scale mean change from baseline (0.1 ± 2.51), the decrease of the Multiple Sclerosis Severity Score from 5.1 ± 2.59 at baseline to 3.9 ± 2.31 at the 60-months follow-up, and the percentage of patients with 'no change' in the Clinical Global Impression scale at the 60-months follow-up (78.11%). Adverse events (AE) occurring in 75.04% of patients were in line with the known safety profile of fingolimod and were mostly non-serious AE (33.62%) and non-serious adverse drug reactions (50.59%; serious AE 4.98%; serious ADR 10.82%).PANGAEA demonstrated the sustained beneficial effectiveness and safety of fingolimod in the long-term real-world treatment of patients with RRMS.

Background: Fingolimod (Gilenya®) is approved for adult and pediatric patients with highly active relapsing–remitting multiple sclerosis (RRMS).Objectives: The objective was to describe the effectiveness of fingolimod in young adults compared to older patients in clinical practice.Methods: PANGAEA is the largest prospective, multi-center, non-interventional, long-term study evaluating fingolimod in RRMS. We descriptively analyzed demographics, MS characteristics, and severity in two subgroups of young adults (≤20 and >20 to ≤30 years) and older patients (>30 years).Results: Young adults had lower Expanded Disability Status Scale (EDSS) scores compared to older patients (1.8 and 2.3 vs. 3.2) at baseline. The mean EDSS scores remained stable over 5 years in all subgroups. Young adults had higher annual relapse rates (2.0 and 1.7 vs. 1.4) at study entry, which were reduced by approximately 80% in all subgroups over 5 years. The proportion of patients with no clinical disease activity in year 4 was 52.6 and 73.4 vs. 66.9% in patients ≤20, >20 to ≤30 years and >30 years, respectively. The symbol digit modalities test score increased by 15.25 ± 8.3 and 8.3 ± 11.3 (mean ± SD) from baseline in patients >20 to ≤30 and >30 years.Conclusions: Real-world evidence suggests a long-term treatment benefit of fingolimod in young RRMS patients.

Patients with multiple sclerosis (MS) suffer from cognitive impairment in 40-70% of the cases. There is evidence that the cognitive status is predictive for working ability and early retirement. Regular assessment of cognitive functionality is therefore urgently needed.The German validation of the Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) battery was evaluated in a multicentric way with respect to its feasibility in private neurological centers across Germany.Physician assistants were trained with respect to application and scoring of BICAMS. All scored test materials were evaluated by independent neuropsychological experts.A total of 1606 BICAMS datasets were collected from 65 neurological centers. Of these 1573 datasets were analyzed of which 49.7% were correctly applied and scored while mistakes in application, scoring and transformation were found in 50.3%. Interrater reliability for each subtest was found to be ICC [Formula: see text] 0.953 when datasets containing mistakes were excluded.In general, BICAMS is highly recommended to be applied in standard clinical care; however, it should be emphasized that although the interrater reliability in the final sample was high, serious mistakes were found in 50.3% of cases. From these findings we conclude that nonpsychological staff have to be even more intensively trained and supervised by experts in the application and scoring of BICAMS.HINTERGRUND: Patienten mit Multipler Sklerose (MS) leiden in 40–70 % der Fälle unter kognitiven Störungen. Der kognitive Status gilt erwiesenermaßen als Prädiktor für Berufsfähigkeit und frühzeitige Berentung. Eine regelmäßige Erfassung der kognitiven Leistungsfähigkeit ist somit dringend indiziert.Die deutsche Fassung der international empfohlenen BICAMS (Brief International Cognitive Assessment for Multiple Sclerosis) -Batterie wurde auf Praktikabilität in der klinischen Routine neurologischer Praxen in Deutschland multizentrisch überprüft.Medizinische Fachangestellte (MFAs) wurden hinsichtlich der Durchführung und Auswertung von BICAMS geschult. Alle ausgewerteten Testbögen wurden von unabhängigen neuropsychologischen Experten überprüft.Insgesamt 1606 BICAMS-Datensätze wurden in 65 Zentren erhoben. Von diesen konnten 1573 analysiert werden. 49,7 % der erhobenen Datensätze wurden inklusive aller Auswerteschritte korrekt durchgeführt. Bei den anderen 50,3 % fanden sich Durchführungs‑, Auswerte- oder Transformationsfehler. Nach Bereinigung der Stichprobe durch fehlerbehaftete Fälle ergaben sich Werte der Interrater-Reliabilität pro Testverfahren in Höhe von ICC [Formula: see text] 0,953.Grundsätzlich ist BICAMS für den Einsatz im klinischen Alltag sehr zu empfehlen. Es bleibt allerdings zu betonen, dass obgleich die Interrater-Reliabilität für die final bereinigte Stichprobe sehr hoch war, im Gesamtdatensatz 50,3 % Durchführungs‑, Auswerte- oder Transformationsfehler gefunden wurden. Daraus lässt sich die Notwendigkeit ableiten, nichtpsychologisches Personal noch eingehender in der Anwendung und Auswertung von BICAMS durch Experten zu schulen und zu supervidieren.

Summary Background No treatment has consistently shown efficacy in slowing disability progression in patients with secondary progressive multiple sclerosis (SPMS). We assessed the effect of siponimod, a selective sphingosine 1-phosphate (S1P) receptor 1,5 modulator, on disability progression in patients with SPMS. Methods This event-driven and exposure-driven, double-blind, phase 3 trial was done at 292 hospital clinics and specialised multiple sclerosis centres in 31 countries. Using interactive response technology to assign numbers linked to treatment arms, patients (age 18–60 years) with SPMS and an Expanded Disability Status Scale score of 3·0–6·5 were randomly assigned (2:1) to once daily oral siponimod 2 mg or placebo for up to 3 years or until the occurrence of a prespecified number of confirmed disability progression (CDP) events. The primary endpoint was time to 3-month CDP. Efficacy was assessed for the full analysis set (ie, all randomly assigned and treated patients); safety was assessed for the safety set. This trial is registered with ClinicalTrials.gov, number NCT01665144. Findings 1651 patients were randomly assigned between Feb 5, 2013, and June 2, 2015 (1105 to the siponimod group, and 546 to the placebo group). One patient did not sign the consent form, and five patients did not receive study drug, all of whom were in the siponimod group. 1645 patients were included in the analyses (1099 in the siponimod group and 546 in the placebo). At baseline, the mean time since first multiple sclerosis symptoms was 16·8 years (SD 8·3), and the mean time since conversion to SPMS was 3·8 years (SD 3·5); 1055 (64%) patients had not relapsed in the previous 2 years, and 918 (56%) of 1651 needed walking assistance. 903 (82%) patients receiving siponimod and 424 (78%) patients receiving placebo completed the study. 288 (26%) of 1096 patients receiving siponimod and 173 (32%) of 545 patients receiving placebo had 3-month CDP (hazard ratio 0·79, 95% CI 0·65–0·95; relative risk reduction 21%; p=0·013). Adverse events occurred in 975 (89%) of 1099 patients receiving siponimod versus 445 (82%) of 546 patients receiving placebo; serious adverse events were reported for 197 (18%) patients in the siponimod group versus 83 (15%) patients in the placebo group. Lymphopenia, increased liver transaminase concentration, bradycardia and bradyarrhythmia at treatment initiation, macular oedema, hypertension, varicella zoster reactivation, and convulsions occurred more frequently with siponimod than with placebo. Initial dose titration mitigated cardiac first-dose effects. Frequencies of infections, malignancies, and fatalities did not differ between groups. Interpretation Siponimod reduced the risk of disability progression with a safety profile similar to that of other S1P modulators and is likely to be a useful treatment for SPMS. Funding Novartis Pharma AG.

The population with multiple sclerosis receiving treatment in clinical practice differs from that in randomized controlled trials (RCTs). An assessment of the real-world benefit–risk profile of therapies is needed. This analysis used data from the large, noninterventional, observational German study Post-Authorization Non-interventional German sAfety study of GilEnyA (PANGAEA) to assess prospectively baseline characteristics and outcomes after 12 months (± 90 days) of fingolimod treatment. Patients were divided into 2 cohorts: fingolimod starter [first received fingolimod in PANGAEA (n = 3315)] and previous study [received fingolimod before enrollment in PANGAEA in RCTs (n = 875), some of whom also had baseline data at entry into RCTs (n = 505)]. At PANGAEA baseline, patients in the fingolimod starter versus the previous study cohort had a higher annualized relapse rate [ARR (95% confidence interval): 1.79 (1.75–1.83) vs 1.32 (1.25–1.40)] and Expanded Disability Status Scale score [3.11 (3.04–3.17) vs 2.55 (2.44–2.66)]. A greater proportion in the fingolimod starter versus previous study cohort had diabetes (2.0% vs 0.7%). After 12 months of fingolimod, ARRs were lower than in the 12 months before PANGAEA enrollment in the fingolimod starter [0.386 (0.360–0.414)] and previous study [0.276 (0.238–0.320)] cohorts. Expanded Disability Status Scale scores were stable versus baseline. Adverse events were experienced by similar proportions in both cohorts during fingolimod treatment. Relevant differences exist in disease activity and comorbidities between patients receiving fingolimod in clinical practice versus RCTs. Irrespective of baseline differences indicating a higher proportion at an advanced stage of multiple sclerosis in the real world versus RCTs, fingolimod remains effective, with a manageable safety profile. Electronic supplementary material The online version of this article (10.1007/s13311-017-0595-y) contains supplementary material, which is available to authorized users.

Background The risk of progressive multifocal leukoencephalopathy limits the duration over which patients can receive natalizumab before requiring a switch to other therapies such as fingolimod. To date, no studies have assessed the long-term real-world effectiveness and safety of fingolimod following a switch from natalizumab. We aimed to investigate the benefit–risk profile of fingolimod over 48 months in patients switching from natalizumab, and the impact of washout duration after natalizumab discontinuation on outcomes during fingolimod treatment. Methods This analysis used data from PANGAEA, an ongoing German multicenter, prospective, non-interventional, observational study. In total, 3912 patients were included: 530 had switched from natalizumab (natalizumab subpopulation), and a reference population of 3382 had switched from other treatments or were treatment-naive (non-natalizumab subpopulation). The natalizumab subpopulation was stratified by washout duration (30–89 days, 90–149 days, and ≥ 150 days) prior to fingolimod initiation. Results In the natalizumab subpopulation over 48 months of fingolimod treatment, 58.2% (n = 227/390) of patients remained on fingolimod. Over this period, mean annualized relapse rates (ARRs) and proportions of patients who relapsed were similar across washout durations, and ranged from 0.455 (95% confidence interval [CI]: 0.363–0.571) to 0.546 (95% CI: 0.446–0.669) and 54.1% (n = 92/170) to 60.2% (n = 127/211), respectively. Overall, 17.1% (n = 36/211) had 6-month confirmed disability worsening. In the non-natalizumab subpopulation, ARR was 0.300, 40.9% (n = 1325/3237) of patients relapsed, and a similar proportion to the natalizumab subpopulation had 6-month disability worsening (16.6% [n = 232/1394]). In both subpopulations, the safety profile of fingolimod was consistent with that observed in randomized controlled trials. Conclusions In patients discontinuing natalizumab, fingolimod has a favorable benefit–risk profile over 48 months. These findings also suggest using a short washout following natalizumab discontinuation, consistent with guidelines and current clinical practice in Germany.

With the proposal of the Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) battery, the need to screen for cognitive deficits within standard clinical care of patients with multiple sclerosis (MS) has been acknowledged. Data regarding how patient characteristics might predict low cognitive performance and therefore require particularly close monitoring is, however, limited so far. We investigated a large, nationwide patient cohort from ambulatory settings, representing the typical distribution of different subtypes, levels of physical disability, and disease durations. Besides cognitive testing with BICAMS, additional sampling of multiple demographics and clinical variables allowed us to characterize general and domain-specific prevalence patterns of cognitive impairment (CI) as well as to delineate which factors are associated with cognitive performance. In a total of 1,094 patients, CI was present in 28% (using a conservative cut-off of the 5th percentile below normative values), with information-processing speed being most frequently affected. Impairment was overall higher in patients with primary progressive (PPMS) and secondary progressive MS than in patients with relapsing-remitting (RR)MS. Regression modelling revealed that disease subtype (i.e., PPMS), long disease duration, high physical disability, unemployment, low educational level, high age, male sex, and the absence of current disease-modifying treatment were important predictors for worse BICAMS' test performance. These results emphasize the importance of continuous cognitive assessment during regular neurological follow-up visits, with a particular focus on patients being identified as high-risk subjects for CI according to the reported factors.

ObjectiveTo assess the long-term real-world benefit–risk profile of fingolimod in patients with relapsing MS in Germany.MethodsThis analysis used data from the noninterventional real-world study, Post-Authorization Non-interventional German sAfety study of GilEnyA (PANGAEA), to assess prospectively the persistence, effectiveness, and safety of fingolimod over 36 months (±90 days) in Germany. For inclusion in the effectiveness analysis (n = 2,537), patients were required to have received fingolimod for the first time in PANGAEA, to have at least 12 months of data, and to have completed each 12-month follow-up period. For the safety analysis (n = 3,266), patients were additionally allowed to have received fingolimod before enrollment.ResultsAt baseline, 94.7% of patients in the effectiveness analysis had received a previous disease-modifying therapy. After 36 months, 70.4% of patients were still receiving fingolimod. Over this period, annualized relapse rates decreased to 0.265 (95% CI: 0.244–0.286) from 1.79 (95% CI: 1.75–1.83), and mean Expanded Disability Status Scale scores remained stable (mean change from baseline: +0.049 [95% CI: −0.015 to +0.114]). In total, 16% of patients had 6-month confirmed disability improvement, 12.5% had 6-month confirmed disability worsening, and 52.4% were free from relapses and 6-month confirmed disability worsening. Adverse events (AEs) and serious AEs were experienced by up to 23.4% and 3.9% of patients, respectively, during any of the 12-month follow-up periods. The frequency and nature of AEs were in line with previous findings.ConclusionsUsing systematically collected data from PANGAEA, this analysis demonstrates the sustained effectiveness, high persistence, and manageable safety profile of fingolimod over 36 months.

BACKGROUND: Although several disease-modifying treatments are available for relapsing multiple sclerosis, treatment effects have been more modest in progressive multiple sclerosis and have been observed particularly in actively relapsing subgroups or those with lesion activity on imaging. We sought to assess whether natalizumab slows disease progression in secondary progressive multiple sclerosis, independent of relapses.METHODS: ASCEND was a phase 3, randomised, double-blind, placebo-controlled trial (part 1) with an optional 2 year open-label extension (part 2). Enrolled patients aged 18-58 years were natalizumab-naive and had secondary progressive multiple sclerosis for 2 years or more, disability progression unrelated to relapses in the previous year, and Expanded Disability Status Scale (EDSS) scores of 3·0-6·5. In part 1, patients from 163 sites in 17 countries were randomly assigned (1:1) to receive 300 mg intravenous natalizumab or placebo every 4 weeks for 2 years. Patients were stratified by site and by EDSS score (3·0-5·5 vs 6·0-6·5). Patients completing part 1 could enrol in part 2, in which all patients received natalizumab every 4 weeks until the end of the study. Throughout both parts, patients and staff were masked to the treatment received in part 1. The primary outcome in part 1 was the proportion of patients with sustained disability progression, assessed by one or more of three measures: the EDSS, Timed 25-Foot Walk (T25FW), and 9-Hole Peg Test (9HPT). The primary outcome in part 2 was the incidence of adverse events and serious adverse events. Efficacy and safety analyses were done in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT01416181.FINDINGS: Between Sept 13, 2011, and July 16, 2015, 889 patients were randomly assigned (n=440 to the natalizumab group, n=449 to the placebo group). In part 1, 195 (44%) of 439 natalizumab-treated patients and 214 (48%) of 448 placebo-treated patients had confirmed disability progression (odds ratio [OR] 0·86; 95% CI 0·66-1·13; p=0·287). No treatment effect was observed on the EDSS (OR 1·06, 95% CI 0·74-1·53; nominal p=0·753) or the T25FW (0·98, 0·74-1·30; nominal p=0·914) components of the primary outcome. However, natalizumab treatment reduced 9HPT progression (OR 0·56, 95% CI 0·40-0·80; nominal p=0·001). In part 1, 100 (22%) placebo-treated and 90 (20%) natalizumab-treated patients had serious adverse events. In part 2, 291 natalizumab-continuing patients and 274 natalizumab-naive patients received natalizumab (median follow-up 160 weeks [range 108-221]). Serious adverse events occurred in 39 (13%) patients continuing natalizumab and in 24 (9%) patients initiating natalizumab. Two deaths occurred in part 1, neither of which was considered related to study treatment. No progressive multifocal leukoencephalopathy occurred.INTERPRETATION: Natalizumab treatment for secondary progressive multiple sclerosis did not reduce progression on the primary multicomponent disability endpoint in part 1, but it did reduce progression on its upper-limb component. Longer-term trials are needed to assess whether treatment of secondary progressive multiple sclerosis might produce benefits on additional disability components.FUNDING: Biogen.

Background Though the Expanded Disability Status Scale (EDSS) is commonly used to assess disability level in relapsing-remitting multiple sclerosis (RRMS), the criteria defining disability progression are used for patients with a wide range of baseline levels of disability in relatively short-term trials. As a result, not all EDSS changes carry the same weight in terms of future disability, and treatment benefits such as decreased risk of reaching particular disability milestones may not be reliably captured. The objectives of this analysis are to assess the probability of confirmed disability worsening to specific EDSS milestones (i.e., EDSS scores ≥3.0, ≥4.0, or ≥6.0) at 288 weeks in the Tysabri Observational Program (TOP) and to examine the impact of relapses occurring during natalizumab therapy in TOP patients who had received natalizumab for ≥24 months. Methods TOP is an ongoing, open-label, observational, prospective study of patients with RRMS in clinical practice. Enrolled patients were naive to natalizumab at treatment initiation or had received ≤3 doses at the time of enrollment. Intravenous natalizumab (300 mg) infusions were given every 4 weeks, and the EDSS was assessed at baseline and every 24 weeks during treatment. Results Of the 4161 patients enrolled in TOP with follow-up of at least 24 months, 3253 patients with available baseline EDSS scores had continued natalizumab treatment and 908 had discontinued (5.4% due to a reported lack of efficacy and 16.4% for other reasons) at the 24-month time point. Those who discontinued due to lack of efficacy had higher baseline EDSS scores (median 4.5 vs. 3.5), higher on-treatment relapse rates (0.82 vs. 0.23), and higher cumulative probabilities of EDSS worsening (16% vs. 9%) at 24 months than those completing therapy. Among 24-month completers, after approximately 5.5 years of natalizumab treatment, the cumulative probabilities of confirmed EDSS worsening by 1.0 and 2.0 points were 18.5% and 7.9%, respectively (24-week confirmation), and 13.5% and 5.3%, respectively (48-week confirmation). The risks of 24- and 48-week confirmed EDSS worsening were significantly higher in patients with on-treatment relapses than in those without relapses. An analysis of time to specific EDSS milestones showed that the probabilities of 48-week confirmed transition from EDSS scores of 0.0–2.0 to ≥3.0, 2.0–3.0 to ≥4.0, and 4.0–5.0 to ≥6.0 at week 288 in TOP were 11.1%, 11.8%, and 9.5%, respectively, with lower probabilities observed among patients without on-treatment relapses (8.1%, 8.4%, and 5.7%, respectively). Conclusions In TOP patients with a median (range) baseline EDSS score of 3.5 (0.0–9.5) who completed 24 months of natalizumab treatment, the rate of 48-week confirmed disability worsening events was below 15%; after approximately 5.5 years of natalizumab treatment, 86.5% and 94.7% of patients did not have EDSS score increases of ≥1.0 or ≥2.0 points, respectively. The presence of relapses was associated with higher rates of overall disability worsening. These results were confirmed by assessing transition to EDSS milestones. Lower rates of overall 48-week confirmed EDSS worsening and of transitioning from EDSS score 4.0–5.0 to ≥6.0 in the absence of relapses suggest that relapses remain a significant driver of disability worsening and that on-treatment relapses in natalizumab-treated patients are of prognostic importance.

Objective The intravenous administration of tromethamine (INN, trometamol) lowers the intracranial pressure in patients with brain edema. One postulated mechanism of action is the increase of the pH of the cerebrospinal fluid. Methods To study tromethamine kinetics in serum and cerebrospinal fluid, nine patients with external ventriculostomies and normal serum creatinine values received 60 mmol intravenous tromethamine (Tris 36.34%, pH 11) over 30 minutes. Serum and cerebrospinal fluid were drawn repeatedly, and concentrations were determined by HPLC. Results Maximum serum concentrations (Cmax) ranged from 211 to 426 mg/L (median, 302 mg/L). The volume of distribution was 0.34 to 0.86 L/kg body weight (median, 0.53 L/kg), and the elimination half-life in serum (t½ β) 3.22 to 8.44 hours (median, 4.53 hours). Cerebrospinal fluid Cmax values ranging from 0.68 to 34.14 mg/L (median, 3.88 mg/L) were observed 1 to 12 hours after the end of the tromethamine infusion (median, 2 hours). AUCCSF/AUCS as a measure of overall cerebrospinal fluid penetration was 0.015 to 0.46 (median, 0.068). Cerebrospinal fluid Cmax and AUCCSF/AUCS depended on the function of the blood–cerebrospinal fluid barrier. Cerebrospinal fluid t½ (8.52 to 14.2 hours; median, 11.2 hours) was substantially longer than the t½ β in serum. In vitro, cerebrospinal fluid concentrations ≤30 mg/L did not influence cerebrospinal fluid pH. Conclusion Tromethamine cerebrospinal fluid concentrations will be high enough to increase the pH of the cerebrospinal fluid only at large doses and in patients with a pronounced disruption of the blood– cerebrospinal fluid barrier. Clinical Pharmacology & Therapeutics (1999) 66, 25–32

The broad antibacterial spectrum and the low incidence of seizures in meropenem-treated patients qualifies meropenem for therapy of bacterial meningitis. The present study evaluates concentrations in ventricular cerebrospinal fluid (CSF) in the absence of pronounced meningeal inflammation. Patients with occlusive hydrocephalus caused by cerebrovascular diseases, who had undergone external ventriculostomy ( n = 10, age range 48 to 75 years), received 2 g of meropenem intravenously over 30 min. Serum and CSF were drawn repeatedly and analyzed by liquid chromatography-mass spectroscopy. Pharmacokinetics were determined by noncompartmental analysis. Maximum concentrations in serum were 84.7 ± 23.7 μg/ml. A CSF maximum ( C maxCSF ) of 0.63 ± 0.50 μg/ml (mean ± standard deviation) was observed 4.1 ± 2.6 h after the end of the infusion. C maxCSF and the area under the curve for CSF (AUC CSF ) depended on the AUC for serum (AUC S ), the CSF-to-serum albumin ratio, and the CSF leukocyte count. Elimination from CSF was considerably slower than from serum (half-life at β phase [ t 1/2β ] of 7.36 ± 2.89 h in CSF versus t 1/2β of 1.69 ± 0.60 h in serum). The AUC CSF /AUC S ratio for meropenem, as a measure of overall CSF penetration, was 0.047 ± 0.022. The AUC CSF /AUC S ratio for meropenem was similar to that for other β-lactam antibiotics with a low binding to serum proteins. The concentration maxima of meropenem in ventricular CSF observed in this study are high enough to kill fully susceptible pathogens. They may not be sufficient to kill bacteria with a reduced sensitivity to carbapenems, although clinical success has been reported for patients with meningitis caused by penicillin-resistant pneumococci and Pseudomonas aeruginosa .

Background First dose observation for cardiac effects is required for fingolimod, but recommendations on the extent vary. This study aims to assess cardiac safety of fingolimod first dose. Individual bradyarrhythmic episodes were evaluated to assess the relevance of continuous electrocardiogram (ECG) monitoring. Methods START is an ongoing open-label, multi-center study. At the time of analysis 3951 patients were enrolled. The primary endpoints are the incidence of bradycardia (heart rate