[Interferon-ß1b in multiple sclerosis therapy: more than 20 years clinical experience]. / Interferon-ß1b in der Multiple-Sklerose-Therapie : Mehr als 20 Jahre klinische Erfahrung.

The introduction of interferon-ß1b in 1993 in the USA and 2 years later in Europe made it possible for the first time to alter the course of the disease in patients with relapsing-remitting multiple sclerosis (MS). Subsequently, interferon-ß1b was approved for the treatment of patients with active secondary progressive MS (1999) and early relapsing-remitting MS following a first demyelinating event (clinically isolated syndrome, CIS) (2006). Here we provide an overview of the clinical experience gathered during more than 20 years of interferon-ß use focusing on long-term efficacy and safety and the impact of early initiation of treatment. Furthermore, the following aspects will be discussed: putative mechanisms of action of interferon-ß, indications for a disease-modifying therapy, clinical relevance of neutralizing antibodies, importance of adherence in MS therapy, high versus low frequency therapy, combination therapies with interferon-ß and safety of interferon-ß in children and adolescents with MS and during pregnancy.

Randomised multicentre trial on safety and efficacy of rivastigmine in cognitively impaired multiple sclerosis patients.

BACKGROUND: Cognitive decline has been recognised as a frequent symptom in multiple sclerosis (MS). Cholinesterase inhibitors (ChEIs) are employed for the treatment of Alzheimer's disease, but there is some evidence that ChEIs might also be effective in MS patients with cognitive deficits, particularly deficits of memory function. OBJECTIVE: The aim of this study was to evaluate efficacy on memory function and safety of the ChEI rivastigmine in MS patients with cognitive deficits as measured by the change from baseline of the total recall score of the selective reminding test (SRT) after 16 weeks of treatment. METHODS: Efficacy and safety of rivastigmine were analysed in a 16-week, multicentre, double-blind, randomised, placebo-controlled study, followed by an optional one-year open-label treatment phase. Effects of rivastigmine and placebo were compared by an analysis of covariance. RESULTS: In total, 86 patients were enrolled. Patients who received rivastigmine (n = 43) showed a non-significant increase in total recall score (sum of all words immediately recalled over all six trials) over placebo (n = 38) after 16 weeks of treatment (p = 0.2576). Other outcome measures provided no evidence supporting benefits of rivastigmine. Treatment with rivastigmine was well tolerated. CONCLUSIONS: With the results of this study, the need for an effective therapy in cognitively impaired MS patients is still required. Thus, intensive and continued clinical research is required to explore therapeutic options for cognitive deficits in MS patients.

[Fingolimod compassionate use program: case study on the concept of a therapy option for multiple sclerosis prior to marketing approval]. / Fingolimod-Compassionate-use-Programm : Fallstudie zum Konzept einer Therapieoption bei Multipler Sklerose vor Zulassung und Markteinführung.

BACKGROUND: In order to meet the needs of therapy of multiple sclerosis (MS) new immune therapies with a user-friendly application and better effectiveness together with good tolerability are necessary. COMPASSIONATE USE: With respect to its potential to improve MS therapy, patients with a high medical need were given access to Fingolimod even before marketing approval. Therefore, a compassionate use program unique in the field of MS was initiated. In total 137 centers participated (75 % outpatient neurologists and 25 % hospitals). Within 19 weeks 135 patients were enrolled to receive Fingolimod. The patients in the compassionate use program can be representatively described as showing hardly controllable disease activity and progression with currently available, often poorly tolerated therapy. The compassionate use program for these patients offered better control of the disease with Fingolimod. The adverse events were as expected. CONCLUSIONS: The Fingolimod compassionate use program demonstrated the need for this new therapeutic option. Patients who were not yet sufficiently treated were provided with an effective therapy with a good safety profile and a user-friendly administration form.

A 24-week, multicentre, open evaluation of the clinical effectiveness of the rivastigmine patch in patients with probable Alzheimer's disease.

BACKGROUND: Cholinesterase inhibitors form the mainstay of treatment for persons with mild-to-moderate Alzheimer's disease (AD). The rivastigmine patch may increase compliance and the proportion of patients maintaining an efficacious dose compared with oral cholinesterase inhibitors. OBJECTIVE: To investigate the proportion of patients who reached and maintained the target rivastigmine patch dose compared with the target rivastigmine capsule dose reported in clinical trials. METHODS: This was a multicentre, 24-week, open-label study in persons with probable AD and a Mini-Mental State Examination (MMSE) score of ≥ 10 and ≤ 26. The primary outcome was the proportion of patients (ITT population) treated with 9.5 mg/24 h rivastigmine patch for at least 8 weeks at week 24. Secondary outcomes included week 24 MMSE, Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC), Trail Making Test Part A (TMT-A) and Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) scores. RESULTS: Overall, 208 participants received treatment and 155 (74.5%) completed the study. Within the ITT population, 147/182 patients (80.8%; 95% CI 75.0-86.5%) were treated for at least 8 weeks with the 9.5 mg/24 h rivastigmine patch; 135/182 patients (74.2%; 95% CI 67.8-80.5%) were treated for at least 8 weeks and completed the study. The most common adverse events were nausea (10.1% of patients), erythema (8.7%), pruritus (8.2%) and vomiting (7.2%). At week 24, patients treated with the rivastigmine patch showed improvements on MMSE, ADCS-ADL, ADCS-CGIC and TMT-A scores. Caregivers reported acceptance, preference and satisfaction with the patch. CONCLUSION: Transdermal delivery may allow more patients to reach and maintain therapeutic doses of rivastigmine compared with oral rivastigmine.

A pharmacokinetic study of two modified-release methylphenidate formulations under different food conditions in healthy volunteers.

OBJECTIVES: Primary objective was to investigate bioequivalence of Ritalin LA(R); 40 mg compared to Medikinet retard 40 mg in healthy male volunteers under fasted and fed conditions. Secondary objectives included assessment of tolerability and determination of further pharmacokinetic parameters. The difference between the kinetic profiles of Ritalin LA(R) and Medikinet retard with respect to breakfast intake was additionally explored. METHODS: 28 subjects were randomized in this open-label, four-treatment, cross-over-design study. Pharmacokinetic evaluations included AUC(0-inf), Cmax, tmax, elimination half life (t1/2) and mean residence time MRT(0-inf)). The relative bioavailability of Ritalin LA(R) and Medikinet retard and the food effect were assessed using a 90% confidence interval (CI) based on the lower and upper endpoints of the CI for the ratios of the geometric means being within the 80 - 125% equivalence criterion. RESULTS: 25 volunteers completed all treatment arms. Frequency of adverse events were comparable for all treatments. Under fasted condition Ritalin LA(R) showed a consistent bimodal concentration time profile with two tmax peaks. Medikinet retard showed a steady absorption with a single tmax peak. The point estimators for AUC(0-inf) and Cmax were found to be 99.7% and 85.9%, respectively. Under fed condition both Ritalin LA(R) and Medikinet retard showed a bimodal concentration time profile with two tmax peaks. The point estimators for AUC(0-inf) and Cmax were estimated as 89.8% and 68.6%, respectively. CONCLUSIONS: Both methylphenidate formulations were safe and well tolerated. Ritalin LA and Medikinet retard were bioequivalent in fasted state but not in fed state. Only Ritalin LA had a biphasic kinetic profile under both fasted and fed conditions. This difference in the kinetic profiles might be of clinical relevance and might offer a potential advantage of Ritalin LA.

Screening for cognitive impairment in Parkinson's disease--which marker relates to disease severity?

The frequency and pattern of cognitive deficits in Parkinson's disease (PD) is under discussion. We assessed 157 consecutive subjects with PD (66.4 +/- 8.9 years (mean +/- standard deviation); average duration of disease 3.5 +/- 1.3 years; average Hoehn and Yahr stage 2.4 +/- 0.9) diagnosed in centers specialized for the diagnosis and treatment of PD with brief tests for memory (Memory Impairment Screen), attention (Letter Sorting Test) and semantic fluency (category animals). Impaired memory was observed in about one half of the subjects regardless of severity of disease as assessed by staging according to Hoehn and Yahr. With greater severity, free recall was impaired and subjects required the cues to recall the items. Performance in the Letter Sorting Test and the semantic fluency task declined with increasing Hoehn and Yahr stage, also. We conclude that cognitive deficits are frequent in PD. Further analyses reveal that even in selected screening tests (e.g. semantic fluency) a significant impairment with increasing disease severity (Hoehn and Yahr stage) as opposed to disease duration alone can be demonstrated.

Spectral composition of NREM sleep in healthy subjects with moderately increased daytime sleepiness.

OBJECTIVE: This study addressed the relationship between daytime sleepiness and spectral composition of the preceding NREM sleep. METHODS: Nineteen healthy volunteers (mean age: 36.5 years; SD: 10.1) underwent polysomnography during two consecutive nights and the multiple sleep latency test (MSLT) on the following day. Daytime sleepiness was also assessed by the Epworth sleepiness scale (ESS). The sleep recordings were visually scored according to standard criteria. The quantitative sleep EEG analysis was performed using a fast Fourier transform routine. The sleep parameters were compared between subjects with short and long MSLT sleep latencies (cut-off=10 min) and between subjects with low and high ESS scores (cut-off=6 points). RESULTS: Subjects with short MSLT sleep latencies showed a reduced theta EEG activity. There was no evidence of reduced synchronization of sleep EEG in subjects with high ESS scores. CONCLUSIONS: Moderately increased daytime sleepiness as indicated by MSLT sleep latency less than 10 min is accompanied by decreased power of theta activity during NREM sleep indicating a deficit of sleep EEG synchronization.

Rhythmic feet movements while falling asleep.

During the wake-sleep transition and sleep, diverse motor phenomena such as hypnagogic foot tremor may occur in the lower extremities. We investigated the relevance of this phenomenon in 375 consecutive subjects examined polysomnographically in a sleep disorders center. Rhythmic feet movements while falling asleep (RFM) were found in 28 subjects (7.5%). RFM occurred mostly as single, short series with a duration of between 10 and 15 seconds. They had a high night-to-night variability and were detected as rhythmic, oscillating movements of the whole foot or toes. Surface electromyographic (EMG) recordings displayed series of repetitive phasic bursts with a periodicity mostly between 1 and 2 per second. Single EMG burst duration varied between 300 and 700 msec. RFM at highest intensity occurred during presleep wakefulness, and usually persisted in sleep stages 1 and 2. RFM did not have a major sleep-disturbing effect in any of the affected subjects. Due to its high prevalence and the lack of a major sleep-disturbing effect, short series of RFM could be considered a quasiphysiological phenomenon. However, in more severe forms of RFM with evidence of a sleep-disturbing effect, RFM should be considered abnormal.

Sudden daytime sleep onset in Parkinson's disease: polysomnographic recordings.

Sleep attacks in Parkinson's disease are controversially discussed. This paper describes a patient with Parkinson's disease suffering from sudden, irresistible onset of sleep during daytime. Medication included levodopa, entacapone, budipine, and cabergoline. Introduction of entacapone was the last therapeutic action preceding onset of sleep events, suggesting increased bioavailabilty of levodopa to be provocative in this case. In contrast to previous cases, the sudden sleep events were witnessed by clinical staff members and documented by polysomnographic and video recordings. Polysomnography during these sleep events remarkably showed abrupt slowing of EEG-background activity and occurrence of slow eye movements and K-complexes within 10 seconds after stable wakefulness. Within 60 seconds, the polysomnographic pattern proceeded to stable sleep stage 2.