Search

Objectives The aim was to assess the efficacy and safety of alprostadil in patients with peripheral arterial occlusive disease (PAOD) Fontaine Stage IV. Methods This was a multinational, prospective, randomised, double blind, placebo controlled, parallel group trial. Patients with Stage IV PAOD were equally randomised to either 4 weeks of alprostadil treatment twice daily or to placebo treatment twice daily. The primary efficacy variables were the rate of complete healing of all necrosis and ulceration 12 weeks after the end of treatment and the frequency of major amputations 24 weeks after the end of treatment. Results A total of 840 patients were randomised between 2004 and 2013. At baseline, no major differences between treatment groups were found. The rate of “complete healing” was 18.4% in patients on alprostadil and 17.2% in patients on placebo. The rates of “major amputations” were 12.6% in patients on alprostadil and 14.6% in patients on placebo. The adjusted difference between alprostadil and placebo including their 95% confidence intervals was 1.1 (−4.0 to 6.3) for “complete healing” and −2.1 (−6.7 to 2.5) for “major amputations.” In the subgroup of diabetic patients the rates of major amputations were numerically lower in the alprostadil than placebo group (10.6% vs. 17.4%). Within the total cohort a non-significant difference in “decrease in ulcer area ≥50%” was reached in 30.2% of patients on alprostadil and in 24.3% of patients on placebo at end of treatment. Conclusions In this study, superiority of alprostadil over placebo could not be shown. Nevertheless, a slight numerical but not clinically relevant advantage for alprostadil emerged from the “area decrease of ulcers by ≥ 50%,” indicating that a healing effect may have started. The results have to be considered in the light of several limitations in study design and conduct.

Background and purpose Dopamine agonists in Parkinson's disease (PD) are associated with impulse control disorders (ICDs) and other compulsive behaviours (together called ICD behaviours). The frequency of ICD behaviours reported as adverse events (AEs) in long-term studies of rotigotine transdermal patch in PD was evaluated. Methods This was a post hoc analysis of six open-label extension studies up to 6 years in duration. Analyses included patients treated with rotigotine for at least 6 months and administered the modified Minnesota Impulse Disorders Interview. ICD behaviours reported as AEs were identified and categorized. Results For 786 patients, the mean (±SD) exposure to rotigotine was 49.4 ± 17.6 months. 71 (9.0%) patients reported 106 ICD AEs cumulatively. Occurrence was similar across categories: 2.5% patients reported ‘compulsive sexual behaviour’, 2.3% ‘buying disorder’, 2.0% ‘compulsive gambling’, 1.7% ‘compulsive eating’ and 1.7% ‘punding behaviour’. Examining at 6-month intervals, the incidence was relatively low during the first 30 months; it was higher over the next 30 months, peaking in the 54–60-month period. No ICD AEs were serious, and 97% were mild or moderate in intensity. Study discontinuation occurred in seven (9.9%) patients with ICD AEs; these then resolved in five patients. Dose reduction occurred for 23 AEs, with the majority (73.9%) resolving. Conclusions In this analysis of >750 patients with PD treated with rotigotine, the frequency of ICD behaviour AEs was 9.0%, with a specific incidence timeline observed. Active surveillance as duration of treatment increases may help early identification and management; once ICD behaviours are present rotigotine dose reduction may be considered.

Background: Monoamine oxidase B (MAO-B) inhibitors and dopamine receptor agonists are common first-line treatment options in early Parkinson’s disease (PD). Objective: To evaluate the efficacy and safety of rotigotine transdermal patch as an add-on therapy to an MAO-B inhibitor in patients with early-PD. Methods: In two Phase III, randomized, double-blind, placebo-controlled studies in early-PD (SP512, SP513), patients were randomized to rotigotine (titrated to optimal dose ≤8 mg/24 h) or placebo, and maintained for 24 (SP512) or 33 (SP513) weeks. Post hoc analyses were performed on pooled data for patients receiving an MAO-B inhibitor (selegiline) at a stable dose at randomization and throughout the studies, with groups defined as “Selegiline+Rotigotine” and “Selegiline+Placebo”. Outcome measures included change from baseline in Unified Parkinson’s Disease Rating Scale (UPDRS) II (activities of daily living), III (motor), UPDRS II+III and responders (patients achieving ≥20%, ≥25% or ≥30% decrease in UPDRS II+III). As post hoc analyses, p-values are exploratory. Results: 130 patients were evaluable for efficacy analyses (“Selegiline+Rotigotine”: 84, “Selegiline+Placebo”: 46). Combined treatment with rotigotine and selegiline improved UPDRS III and UPDRS II+III scores versus selegiline alone (LS-mean [95% CI] treatment difference for UPDRS III: –4.89 [–7.87 to –1.91], p = 0.0015; for UPDRS II+III: –5.76 [–9.71 to –1.82], p = 0.0045). Higher proportion of patients in the “Selegiline+Rotigotine” group were classified as ≥20%, ≥25% or ≥30% responders (all p 65 years (although patient numbers in the subgroups were low). Adverse event profile was consistent with the known safety profile of rotigotine. Conclusions: In these post hoc analyses, adjunctive treatment with rotigotine in patients already receiving an MAO-B inhibitor improved UPDRS II+III score; this appeared to be largely driven by improvements in the motor aspects of PD.

Objective A new and unique methodology was developed to evaluate the association between periodic limb movements (PLMs) and nocturnal blood pressure (BP) excursions in patients with restless legs syndrome (RLS). Methods All data were collected at baseline of the ENCORE (Effects of Neupro on Cardiovascular Observations in Patients with Restless Legs Syndrome) study, a placebo-controlled polysomnographic study of rotigotine in patients with idiopathic RLS. Continuous beat-by-beat BP and heart rate assessments were performed during a full night of polysomnography. All BP elevations occurring with and without PLMs were systematically identified and analyzed. Results Patients ( n = 89) had a mean total of 508.9 ± 405.7 PLMs, 788.4 ± 261.9 systolic BP elevations, and 349.7 ± 242.9 diastolic BP elevations during the night. Higher time-adjusted frequencies of systolic BP elevations [mean difference (95% confidence interval, CI): 543.0 (487.2, I); p 0.0001] and diastolic BP elevations (205.8 (169.3, I); p 0.0001) were observed with PLMs than without PLMs. A peak in the frequency of PLM onset coincided with BP elevation onset. Conclusion Our methodology allowed the first evaluation of the total number of nocturnal PLM-associated BP elevations occurring in patients with RLS. Our data clearly indicate an interdependence between BP elevations and PLMs, and they have clinical relevance as BP variability is a potential cardiovascular risk factor.

Introduction Gastrointestinal (GI) symptoms are common among patients with Parkinson's disease (PD), due to both the disease itself and anti-PD drugs. We hypothesized that transdermal drug administration may result in fewer GI problems. This prospective observational study (ClinicalTrials.gov: NCT01159691 ) investigated effect of switching to rotigotine transdermal patch from oral anti-PD medications in patients with PD and existing GI symptoms. Methods Patients were enrolled if their physician was planning to switch them to rotigotine because of GI symptoms experienced while receiving oral anti-PD medications. Effectiveness assessments included a visual analog scale (VAS) measuring intensity of GI symptoms from 0 (no disorder) to 100 mm (extremely severe disorder), a questionnaire on the frequency and intensity of six individual GI complaints (heartburn, bloating, nausea, vomiting, abdominal pain, diarrhea), each rated 0–12 for a sum score of 0–72, and patient satisfaction regarding GI symptoms over approximately 6 weeks after switching. Results Of 75 patients who received rotigotine, 58 had follow-up data available for final analysis. Intensity of GI complaints improved numerically on both the VAS (47.5 ± 24.4 mm [ n = 65] at baseline, 19.7 ± 23.3 mm [ n = 58] after around 6 weeks) and the sum score of GI complaints (11.2 ± 9.0 at baseline, 2.1 ± 4.4 [ n = 58] after around 6 weeks). Fifty of 58 patients were “satisfied” or “very satisfied” regarding GI symptoms over around 6 weeks following switch to the patch. Conclusion This study suggests that a switch from oral anti-PD medications to rotigotine transdermal patch may improve existing GI symptoms among patients with PD. Additional controlled studies are needed to confirm this finding.

Background The SP790 study (ClinicalTrials.gov, NCT00136045 ) showed benefits of rotigotine over placebo in improving symptom severity of restless legs syndrome (RLS), also known as Willis-Ekbom disease, on the International Restless Legs Syndrome Study Group rating scale (IRLS), Clinical Global Impression item 1 (CGI-1), RLS 6-item questionnaire (RLS-6), and the RLS-quality of life questionnaire (RLS-QoL) in patients with moderate to severe idiopathic RLS. To provide clinical context for the IRLS and to guide the choice of assessment scales for RLS studies, our post hoc analysis of SP790 data evaluated associations between the IRLS and the CGI-1, IRLS and RLS-6, and the IRLS and RLS-QoL. Methods Scale associations were analyzed at baseline and at the end of maintenance (EoM) using data from the safety set (rotigotine and placebo groups combined [ n = 458]). Changes from baseline to EoM in IRLS score vs comparator scale scores also were analyzed. Results There was a trend towards increasing IRLS severity category with increasing CGI-1, RLS-6, and RLS-QoL score. Pearson product moment correlation coefficients showed correlations between IRLS and comparator scale scores at baseline and EoM as well as correlations for change from baseline to EoM. Conclusion Correlations between the IRLS and comparator scales were substantial. These data indicate that the IRLS is clinically meaningful. The IRLS and CGI-1 are generally sufficient to evaluate the overall severity and impact of RLS symptoms in clinical trials.

Objective We aimed to assess effectiveness and tolerability of rotigotine in patients with moderate to severe idiopathic restless legs syndrome (RLS) under daily practice conditions in Germany. Methods In this 3-month noninterventional study, effectiveness was assessed using RLS-6 (primary variables were symptom severity when falling asleep [item 2] and during the night [item 3]). Data were collected at baseline and at the end of treatment. Safety assessments included adverse events (AEs). Results Six hundred and eighty-four patients were treated with rotigotine and 418 (61%) completed the study. The full analysis set (FAS) comprised 564 patients (106 de novo; 458 pretreated [454 had complete rotigotine dosing data]). Mean rotigotine dose of longest duration was 2.4 ± 1.4 mg/24 h. Rotigotine improved all RLS-6 items (mean change from baseline [item 2], −2.4 ± 3.6; [item 3], −2.7 ± 3.4), with the most pronounced improvement observed in daytime symptoms while at rest (item 4, −2.9 ± 3.2). AEs were typical of dopaminergic treatment and transdermal administration. De novo patients generally started rotigotine on 1 mg/24 h (85% [90/106]) and pretreated patients on 1 (50% [227/454]) or 2 mg/24 h (40% [183/454]). Most patients who were pretreated with levodopa (57%), pramipexole (84%), or ropinirole (78%) monotherapy discontinued these medications on initiation of rotigotine. Conclusions Rotigotine was effective and well-tolerated when used in routine clinical practice.

In many patients with Parkinson's disease (PD), the long-term use of levodopa becomes complicated by the development of motor complications including “wearing-off” fluctuations and drug-induced dyskinesias.1–4 Fluctuations in medication response, characterized by the intermittent reappearance of PD motor symptoms (eg, motor tremor, slowness, stiffness), may be predictable, such as “wearing-off” symptoms that occur toward the end of levodopa dosing, or may be more unpredictable, such as those related to levodopa failing to provide the anticipated therapeutic benefit (dose failure) and those unrelated to levodopa dosing.5 Motor complications associated with levodopa use also often include dyskinesias; indeed, nearly 40% of patients will develop dyskinesias after approximately 5 years of levodopa therapy.1,4 Motor fluctuations are often the most troublesome complaints by patients with longstanding PD,6 and patients with “wearing-off”–related symptoms report worse quality of life than patients without such symptoms.7 Adjunctive therapy with dopamine receptor agonists, catechol-O-methyltransferase inhibitors, or monoamine oxidase B inhibitors reduce “off” time and improve Unified Parkinson's Disease Rating Scale scores in patients with PD who develop motor complications while receiving levodopa therapy.8,9 Although indirect comparisons of studies suggest that adjunctive treatment with dopamine receptor agonists may be more effective than adjunctive treatment with catechol-O-methyltransferase or monoamine oxidase B inhibitors in reducing motor fluctuations, the available comparisons have not observed relevant differences between different dopamine receptor agonists.9 Rotigotine is a nonergolinic dopamine receptor agonist with activity across D1 through D5 receptors, as well as select adrenergic and serotonergic receptors.10 A pharmacokinetic analysis has demonstrated that transdermal delivery maintains stable plasma levels of rotigotine for 24 hours with a daily application.11 Efficacy of rotigotine transdermal patch in patients with advanced PD has been observed in 3 major phase 3 studies when used as add-on therapy to levodopa (CLEOPATRA-PD,12 PREFER,13 and SP92114). All 3 studies reported significant reduction from baseline to end of maintenance (EoM) in absolute daily “off” time versus placebo as assessed by patient home diary data (the primary efficacy variable). Improvements in absolute daily time spent “on” and “on without troublesome dyskinesia” (secondary variables) from baseline to EoM were also reported.12–14 Although the improvement in motor fluctuations in patients with advanced PD has been demonstrated in terms of overall change from baseline to EoM, the time course of effectiveness over the entire rotigotine 24-hour drug delivery range has not been analyzed. Therefore, the objective of this post hoc analysis was to examine the time course of the efficacy profile over the entire 24-hour range of a day in patients with advanced PD, based on further analysis of the patient home diary data. These analyses were performed to better understand, from the patients' perspective, how the benefit provided by rotigotine is distributed during the course of the morning, afternoon, and evening.

This 12 week double-blind, placebo-controlled study (ClinicalTrials.gov: NCT01569464) was conducted to evaluate the effects of rotigotine transdermal patch on daytime symptoms in patients with idiopathic restless legs syndrome (RLS).Adult patients with moderate-to-severe RLS were randomized to rotigotine (optimal dose: 1-3 mg/24 h) or placebo. A modified four-assessment version (4:00 pm, 6:00 pm, 8:00 pm, and 10:00 pm) of the Multiple Suggested Immobilization Test (m-SIT) was performed at baseline and end of 4 week maintenance (EoM). Primary study outcomes were change from baseline to EoM in International Restless Legs Syndrome Rating Scale (IRLS) and in average of means for the m-SIT Discomfort Scale (m-SIT-DS) (combined average of mean values from each of the individual assessments). Secondary outcomes included average of means of Periodic Limb Movement during Wakefulness Index (PLMWI; PLM/hour) for the combination of m-SIT.A total of 150 patients were randomized and 137 (rotigotine: 92/101 [91.1%]; placebo: 45/49 [91.8%]) completed maintenance. All 150 randomized patients were assessed for efficacy. At EoM, mean change in IRLS was -14.9 ± 9.3 with rotigotine vs. -12.7 ± 7.6 with placebo (ANCOVA, LS mean treatment difference [95% CI]: -0.27 [-2.96, 2.42]; p = 0.8451). Changes in average of means of m-SIT-DS values of each individual SIT were comparable with rotigotine (-2.68 ± 2.31) vs. placebo (-2.62 ± 2.61) (ANCOVA, LS mean treatment difference [95% CI]: 0.07 [-0.61, 0.75]; p = 0.8336) and comparable reductions in PLMWI were observed in both treatment groups (8.34 [-8.50, 25.17]; p = 0.3290). Rotigotine was generally well tolerated. Application site reactions (rotigotine: 20 patients [19.8%]; placebo: 4 [8.2%]) and nausea (16 [15.8%]; 3 [6.1%]) were the most common AEs.Rotigotine was beneficial in improving overall RLS symptom severity (assessed by IRLS) and RLS symptom severity at various times of the day (m-SIT-DS); however, superiority to placebo was not established.

To provide real-world data on caregiver and physician perceptions of the advantages and disadvantages of rotigotine transdermal patch (Neupro * ) versus oral Parkinson's Disease (PD) medication.Cross-sectional, non-interventional study in routine clinical practice in Germany (NCT01330290). Patients had PD with documented need for care, and had received rotigotine transdermal patch as add-on to oral PD treatment for ≥1 month. Caregivers/nurses and physicians assessed rotigotine transdermal patch versus oral PD medications using questionnaires. Specific questions regarding the possible benefits of transdermal application were asked and comprised questions on: swallowing dysfunction, nausea/vomiting, monitoring therapy, once daily application, application independently from meals, application to sleeping patients, caregiving efforts (caregivers only) and clinical aspects (physicians only). Each question was assessed on a 5 point scale ranging from -2 (major disadvantage) to 2 (major advantage) compared with oral treatment. Primary outcomes were mean total scores of all questions for caregivers/nurses and physicians who provided responses for ≥4 questions. As there are no validated tools to assess physician/caregiver preference in the PD setting, there is no reference against which the current findings can be compared; this study serves to pilot the questionnaires.Questionnaire responses from 128 caregivers/nurses and 41 physicians were documented for 147 patients. One hundred (68%) patients had a caregiving family member; 40 (27%) were cared for by a nurse. Mean PD duration was 8.2 (SD 6.3) years; 136 (93%) patients were taking levodopa. Mean total score of caregivers'/nurses' questionnaires was 1.32 (SD 0.67) and of physicians' questionnaires was 1.46 (0.32) indicating a perceived advantage of rotigotine transdermal patch over oral PD therapy. Mean scores for individual questions were in the range 1.03-1.54 for caregivers/nurses and 1.15-1.87 for physicians. When given a choice about rationale to prescribe, physicians cited pharmaceutical form (patch) in 139 (95%) cases and active agent (rotigotine) in 89 (61%) cases.Caregivers/nurses and physicians perceived advantages with rotigotine transdermal patch compared to an oral PD medication as add-on therapy in patients with PD; advantages were observed in aspects of medical treatment as well as in everyday situations of caregiving of PD patients.

Objective: This double-blind, placebo-controlled, interventional trial was conducted to investigate the effects of rotigotine patch on periodic limb movement (PLM)–associated nocturnal systolic blood pressure (SBP) elevations. Methods: Patients with moderate to severe restless legs syndrome (RLS) were randomized to rotigotine (optimal dose [1–3 mg/24 h]) or placebo. Continuous beat-to-beat blood pressure (BP) assessments were performed during polysomnography at baseline and at the end of 4-week maintenance. Primary outcome was change in number of PLM-associated SBP elevations (defined as slope of linear regression ≥2.5 mm Hg/beat-to-beat interval over 5 consecutive heartbeats [≥10 mm Hg]). Additional outcomes were total SBP elevations, PLM-associated and total diastolic BP (DBP) elevations, periodic limb movements index (PLMI), and PLM in sleep arousal index (PLMSAI). Results: Of 81 randomized patients, 66 (37 rotigotine, 29 placebo) were included in efficacy assessments. PLM-associated SBP elevations were significantly reduced with rotigotine vs placebo (least squares mean treatment difference [95% confidence interval (CI)] −160.34 [−213.23 to −107.45]; p < 0.0001). Rotigotine-treated patients also had greater reduction vs placebo in total SBP elevations (−161.13 [−264.47 to −57.79]; p = 0.0028), PLM-associated elevations (−88.45 [−126.12 to −50.78]; p < 0.0001), and total DBP elevations (−93.81 [−168.45 to −19.16]; p = 0.0146), PLMI (−32.77 [−44.73 to −20.80]; p < 0.0001), and PLMSAI (−7.10 [−11.93 to −2.26]; p = 0.0047). Adverse events included nausea (rotigotine 23%; placebo 8%), headache (18% each), nasopharyngitis (18%; 8%), and fatigue (13%; 15%). Conclusions: Further investigation is required to determine whether reductions in nocturnal BP elevations observed with rotigotine might modify cardiovascular risk. Classification of evidence: This study provides Class I evidence that for patients with moderate to severe RLS, rotigotine at optimal dose (1–3 mg/24 h) reduced PLM-associated nocturnal SBP elevations.

Determine the minimal clinically important change (MCIC), a measure determining the minimum change in scale score perceived as clinically beneficial, for the international restless legs syndrome (IRLS) and restless legs syndrome 6-item questionnaire (RLS-6) in patients with moderate to severe restless legs syndrome (RLS/Willis-Ekbom disease) treated with the rotigotine transdermal system.This post hoc analysis analyzed data from two 6-mo randomized, double-blind, placebo-controlled studies (SP790 [NCT00136045]; SP792 [NCT00135993]) individually and as a pooled analysis in rotigotine-treated patients, with baseline and end of maintenance IRLS and Clinical Global Impressions of change (CGI Item 2) scores available for analysis. An anchor-based approach and receiver operating characteristic (ROC) curves were used to determine the MCIC for the IRLS and RLS-6. We specifically compared "much improved vs minimally improved," "much improved/very much improved vs minimally improved or worse," and "minimally improved or better vs no change or worse" on the CGI-2 using the full analysis set (data as observed).The MCIC IRLS cut-off scores for SP790 and SP792 were similar. Using the pooled SP790+SP792 analysis, the MCIC total IRLS cut-off score (sensitivity, specificity) for "much improved vs minimally improved" was -9 (0.69, 0.66), for "much improved/very much improved vs minimally improved or worse" was -11 (0.81, 0.84), and for "minimally improved or better vs no change or worse" was -9 (0.79, 0.88). MCIC ROC cut-offs were also calculated for each RLS-6 item.In patients with RLS, the MCIC values derived in the current analysis provide a basis for defining meaningful clinical improvement based on changes in the IRLS and RLS-6 following treatment with rotigotine.

Although dopamine agonists (DAs) are sometimes perceived as poorly tolerated by the elderly, there is little clinical evidence to support these concerns. Safety and tolerability of rotigotine have been demonstrated in four 6-month randomized placebo-controlled studies: two in early Parkinson's disease (PD) and two in advanced PD. A post hoc analysis of data from these pivotal trials was carried out to compare the adverse event (AE) profiles of younger and older patient populations. Data from early and advanced PD trials were separately pooled and evaluated using two age cut-offs (

Background A recent trial involving predominantly Caucasian subjects with Parkinson Disease (PD) showed switching overnight from an oral dopaminergic agonist to the rotigotine patch was well tolerated without loss of efficacy. However, no such data have been generated for Korean patients. Methods This open-label multicenter trial investigated PD patients whose symptoms were not satisfactorily controlled by ropinirole, at a total daily dose of 3 mg to 12 mg, taken as monotherapy or as an adjunct to levodopa. Switching treatment from oral ropinirole to transdermal rotigotine was carried out overnight, with a dosage ratio of 1.5:1. After a 28-day treatment period, the safety and tolerability of switching was evaluated. Due to the exploratory nature of this trial, the effects of rotigotine on motor and nonmotor symptoms of PD were analyzed in a descriptive manner. Results Of the 116 subjects who received at least one treatment, 99 (85%) completed the 28-day trial period. Dose adjustments were required for 11 subjects who completed the treatment period. A total of 76 treatment-emergent adverse events (AEs) occurred in 45 subjects. No subject experienced a serious AE. Thirteen subjects discontinued rotigotine prematurely due to AEs. Efficacy results suggested improvements in both motor and nonmotor symptoms and quality of life after switching. Fifty-two subjects (46%) agreed that they preferred using the patch over oral medications, while 31 (28%) disagreed. Conclusions Switching treatment overnight from oral ropinirole to transdermal rotigotine patch, using a dosage ratio of 1.5:1, was well tolerated in Korean patients with no loss of efficacy. Trial registration This trial is registered with the ClincalTrails.gov Registry (NCT00593606).

Introduction Rotigotine transdermal system reduces periodic leg movements (PLM) during sleep in patients with restless legs syndrome (RLS). Episodic nocturnal blood pressure (BP) excursions coincide with PLM, possibly increasing the risk of hypertension and cardiovascular disease. We examined the effect of rotigotine on PLM-associated and total nocturnal systolic BP (NSBP) elevations in patients with moderate-to-severe RLS (IRLS ⩾ 15). Materials and methods This double-blind, placebo-controlled study (SP0977 ENCORE [NCT01455012]) randomized patients (1:1) to optimal dose rotigotine (1–3 mg/24 h) or placebo. Continuous beat-by-beat BP and heart rate assessments were performed at baseline and end of 4-week maintenance (EoM). Primary outcome was change from baseline to EoM in PLM-associated NSBP elevations (defined: a slope of linear regression ⩾2.5 over 5 consecutive heartbeats [equivalent to ⩾10 mmHg]). Change in total NSBP elevations and PLM index (PLMI) were also assessed. Efficacy data are reported for the full analysis set (FAS). Results 81 patients (mean ± SD age: 57.2 ± 10.5 years; 63% female) were randomized (rotigotine: 40; placebo: 41); 66 (rotigotine: 37; placebo: 29) comprised the FAS. Mean (±SD) baseline PLMI was similar between rotigotine (72.9 ± 55.6) and placebo (69.9 ± 47.9). Reductions from baseline (∼300 elevations) in PLM-associated NSBP elevations were greater with rotigotine vs. placebo (LS mean [95% CI]: −239.95 [−275.34, −204.56] vs −79.61 [119.25, −39.97]; treatment difference: −160.34 [−213.23, −107.45]; p p = 0.0028). Greater decreases from baseline to EoM in PLMI were observed for rotigotine (−49.4 [−57.4, −41.4]) vs. placebo (−16.6 [−25.6, −7.7]) (−32.8 [−44.7, −20.8]; p Conclusion Rotigotine reduced PLM-associated and total NSBP elevations in patients with RLS. Further investigation is required to determine whether decreases in PLMI-related and total nocturnal BP translate into reductions in cardiovascular risk in patients with RLS. Acknowledgement This study was supported by UCB Pharma, Monheim am Rhein, Germany.

Gender is known to have an influence on medical treatment and the prescribing and outcome of drug treatment. This has also been suggested for selective serotonin reuptake inhibitors (SSRIs). To examine sex differences in the treatment with the SSRI sertraline in routine treatment of depression, data from a 6-month prospective drug utilization observation study on 3,858 women and 1,594 men were analysed for gender differences. Compared to men, women were more often treated by a general practitioner, were somewhat older, had a later onset of illness, were more likely to suffer from a recurrent rather than a first episode of depression, had been treated for depression before, and showed more anxious and less neurasthenic or retarded syndromes. There was no difference regarding duration of the present episode or severity of illness. The mean prescribed dose of sertraline was marginally lower for females compared to males (45.5 versus 46.5 mg/day) with no difference in the rate of psychoactive concomitant medication (6.76% versus 6.80%). There was no difference in side-effects, treatment termination or treatment response.

In patients having undergone orthotopic liver transplantation, the combination of lamivudine plus human hepatitis B immunoglobulin (HBIg), usually given by the intravenous (i.v.) route, is the most effective prophylaxis against the recurrence of the hepatitis B virus [7]. The availability of a subcutaneous (s.c.) preparation would enable these patients to self-administer their required HBIg dose and thereby provide savings in health care costs as a result of a reduced number of visits to the physician [3]. However, when the standard i.v. preparations are used, a dose of approximately 2000 IU, corresponding to a volume of 40 ml, has to be given every 4–6 weeks. To be suitable for s.c. application, the HBIg preparation must contain a higher concentration per milliliter of the antibody to hepatitis B surface antigen (anti-HBs). We therefore investigated the tolerability and pharmacokinetics of the novel HBIg BT088 (manufacturer Biotest AG, Dreieich, Germany), which contains 635 IU anti-HBs/ ml [1], in male and female healthy volunteers after s.c. and intramuscular (i.m.) administration, since both application routes may offer advantages for patients. After approval of the protocol by the local ethics committee, written informed consent was obtained from each volunteer enrolled into this open, randomised, parallel group study. Thirty healthy volunteers (15 females) with baseline anti-HBs concentrations below 0.002 IU/ml were enrolled; they received a single dose of BT088 at 30 IU/kg body weight either s.c. (SC-Group) or by the i.m. route (IM-Group). Blood samples for determination of anti-HBs serum concentrations were drawn before the administration of BT088, and at specified time points following its administration: 1, 3 and 6 h (first day), 24 h (day 2) and on days 3, 5, 8, 12, 18, 22, 29, 43, 57 and 71. Measurements of antiHBs concentrations were performed in duplicate using an enzyme-linked immunoassay (AUSAB, Abbott, Germany) as described previously [9, 10]. Pharmacokinetic parameters for anti-HBs were calculated using WINNONLIN PROFESSIONAL ver. 4.1 (Pharsight, Cary, N.C.) as in earlier studies [10]. For comparison with pharmacokinetic parameters obtained in previous trials [9, 10], Cmax and AUC0−∞ were further dose-normalised for a dose of 1000 IU as described earlier [10]. Descriptive statistical analyses (mean, standard deviation, median) were performed using the SAS System for Windows, release 8.2 (SAS Institute, Cary. N.C.). The pharmacokinetic parameters are given in Table 1. Protective levels above 0.1 IU/ml [2] were achieved as early as 20.4±7.5 h (median: 23.8 h; range: 6.0–24.2 h) after s.c. application and at 19.9±8.2 h (median: 24.0 h; range: 1.0–24.1 h) after i.m. injection. No serious adverse events occurred during the study, and only mild reactions at the injection site appeared in four volunteers. Comparable serum concentrations were obtained over the observation period using both administration routes. The mean terminal elimination half-lives (t1/2el) of 23 days correspond to that of normal human IgG [5] and are in accordance with data of HBIg for i.v. administration in healthy volunteers [9] and in patients with multiple myeloma or chronic leukaemia [10]. Comparable halflives were obtained after i.m. administration of HBIg of P. A. Thurmann (*) . J. Szymanski . S. Haffner . U. Tenter Philipp Klee-Institute of Clinical Pharmacology, HELIOS Klinikum Wuppertal, University Witten/Herdecke, Heusnerstr. 40, 42283 Wuppertal, Germany e-mail: pthuermann@wuppertal.helios-kliniken.de Tel.: +49-202-8961851 Fax: +49-202-8961852