One year open-label safety and efficacy trial with rotigotine transdermal patch in moderate to severe idiopathic restless legs syndrome

BackgroundLong-term efficacy and tolerability data are not yet available for patch formulations of dopamine agonists in restless legs syndrome.MethodsEfficacy and safety of rotigotine (0.5–4 mg/24 h), formulated as a once-daily transdermal system (patch), were investigated in an open extension (SP710) of a preceding 6-week placebo-controlled trial (SP709, 341 randomized patients) in patients with idiopathic restless legs syndrome. For efficacy assessment the international RLS severity scale (IRLS), the RLS-6 scales, the clinical global impressions (CGI) and the QoL-RLS questionnaire were administered. In addition, long-term tolerability and safety were assessed.ResultsOf 310 patients who finished the controlled trial, 295 (mean age 58 ± 10 years, 66% females) with a mean IRLS score of 27.8 ± 5.9 at baseline of SP709 were included. We report results after one year of this ongoing long-term trial. Two hundred twenty patients (retention rate = 74.6%) completed the 12-month follow-up period. The mean daily dose was 2.8 ± 1.2 mg/24 h with 4 mg/24 h (40.6%) being the most frequently applied dose; 14.8% were sufficiently treated with 0.5 or 1.0 mg/24 h. The IRLS total score improved by −17.4 ± 9.9 points between baseline and end of Year 1 (p < 0.001). The other measures of severity, sleep satisfaction and quality of life supported the efficacy of rotigotine (p < 0.001 for pre-post-comparisons of all efficacy variables). The tolerability was described as “good” or “very good” by 80.3% of all patients. The most common adverse events were application site reactions (40.0%), which led to withdrawal in 13.2%. Further relatively frequent adverse events were nausea (9.5%) and fatigue (6.4%). Two drug-related serious adverse events, nausea and syncope, required hospitalization. Symptoms of augmentation were not reported by the patients.ConclusionRotigotine provided a stable, clinically relevant improvement in all efficacy measures throughout one year of maintenance therapy. The transdermal patch was safe and generally well tolerated by the majority of patients. Comparable to any transdermal therapy, application site reactions were the main treatment complication.     

Efficacy of rotigotine for treatment of moderate-to-severe restless legs syndrome: a randomised, double-blind, placebo-controlled trial

BACKGROUND: Continuous administration of a dopamine agonist could be used to treat patients with restless legs syndrome. Our aim was to investigate the efficacy of transdermal rotigotine in the treatment of idiopathic restless legs syndrome. METHODS: In this randomised, double-blind, placebo-controlled trial, 458 patients with moderate-to-severe idiopathic restless legs syndrome (average baseline International Restless Legs Syndrome Study Group severity rating scale [IRLS] sum score of 28.1) were randomly assigned to receive transdermal rotigotine 1 mg over 24 h (n=115), 2 mg over 24 h (n=112), or 3 mg over 24 h (n=114), or to receive placebo (n=117). Study medication was delivered via patches, applied once a day for 6 months. Randomisation was done with a computer-generated randomisation list, stratified by centre. Primary efficacy outcomes were absolute change from baseline to end of maintenance in IRLS sum score and in the clinical global impressions (CGI) item 1 score, assessed by analysis of covariance in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT00136045. FINDINGS: Efficacy analyses were done on 112 patients in the 1 mg group, 109 in the 2 mg group, 112 in the 3 mg group, and 114 in the placebo group. Mean change in IRLS sum score from baseline at the end of the maintenance phase was -13.7 (SE 0.9) in the 1 mg group, -16.2 (0.9) in the 2 mg group, -16.8 (0.9) in the 3 mg group, and -8.6 (0.9) in the placebo group (p<0.0001 for treatment difference vs placebo with each dose). Mean change in CGI item 1 score from baseline at the end of the maintenance phase was -2.09 (0.14) in the 1 mg group, -2.41 (0.14) in the 2 mg group, -2.55 (0.14) in the 3 mg group, and -1.34 (0.14) in the placebo group (p<0.0001 for treatment difference vs placebo with each dose). Skin reactions, mostly mild or moderate, were seen in 145 (43%) of 341 patients who received rotigotine and in two (2%) of 117 who received placebo. Ten patients had serious adverse event that were deemed to be related to rotigotine: elevation of liver enzymes (one patient), worsening of tinnitus (one patient), non-response to anticoagulation (one patient), electrocardiogram changes (one patient), and application-site reactions (six patients). No admissions to hospital were needed for the application-site reactions, and they all resolved within a short time of patch removal without any other therapeutic intervention. The rate of typical dopaminergic side-effects in patients who received rotigotine was low; no signs of augmentation were noted. INTERPRETATION: 24 h transdermal delivery of low-dose rotigotine could be used to relieve the night-time and daytime symptoms of restless legs syndrome. FUNDING: Schwarz Biosciences.     

合欢皮中新皂甙的结构鉴定

从合欢皮(Albizziae cortex)的95%乙醇提取物的正丁醇萃取部分中分离得到3个新的三萜皂甙,用化学方法及¹H-和¹³C-NMR,DEPT,COSY,TOCSY,HMQC-COSY,HMQC-TOCSY,HMBC,NOESY等波谱方法鉴定其结构为:I(1个三萜,9个糖,2个单萜),命名为合欢皂甙(julibroside)J₁;II(1个三萜,8个糖,2个单萜),命名为合欢皂甙J_{2;II(1个三萜,9个糖,2个单萜),命名为合欢皂甙J3。}     

Intraoperative 3 T MRI is more correlative to residual disease extent than early postoperative MRI

Journal of Neuro-Oncology - Evidence-based, clinical practice guidelines in the management of central nervous system tumors (CNS) continue to be developed and updated through the work of the Joint...     

Elevation of serum cystathionine levels in patients with cobalamin and folate deficiency

Homocysteine can be methylated to form methionine by the cobalamin- (Cbl) and folate-dependent enzyme, methionine synthase; serum levels of total homocysteine are elevated in greater than 95% of patients with either Cbl or folate deficiency. Homocysteine can also condense with serine to form cystathionine in a pyridoxal phosphate-dependent reaction catalyzed by cystathionine beta-synthase. Cystathionine is subsequently cleaved to cysteine and alpha-ketobutyrate by the pyridoxal phosphate-dependent enzyme gamma-cystathionase. To assess levels of cystathionine in Cbl and folate deficiency, we developed a new capillary gas chromatographic-mass spectrometric assay and measured cystathionine in the serum of normal subjects and patients with clinically confirmed deficiencies of these vitamins. The normal range for serum cystathionine was 65 to 301 nmol/L (median = 126 nmol/L) for 50 normal blood donors. In 30 patients with clinically confirmed Cbl deficiency, values for cystathionine ranged from 208 nmol/L to 2,920 nmol/L (median = 816 nmol/L) and 26 (87%) had levels above the normal range. In 20 patients with clinically confirmed folate deficiency, cystathionine concentrations ranged from 138 nmol/L to 4,150 nmol/L (median = 1,560 nmol/L) and 19 (95%) had values above the normal range. Five homozygotes for cystathionine beta-synthase deficiency had high values for serum-total homocysteine and low or low-normal values for serum cystathionine that ranged from 30 nmol/L to 114 nmol/L even though they were on treatment with pyridoxine and had partially responded. One patient with a defect in the synthesis of 5-CH3- tetrahydrofolate and five patients with defects in the synthesis of CH3- Cbl had high values for serum-total homocysteine and high values for cystathionine that ranged from 311 nmol/L to 1,500 nmol/L even though they were on treatment with folic acid and Cbl, respectively, and had partially responded. We conclude that levels of cystathionine are evaluated in the serum of most patients with Cbl and folate deficiency and that they are useful in the differential diagnosis of an elevated serum-total homocysteine level.     

Acquired immunodeficiency syndrome-associated non-Hodgkin's lymphomas and other malignancies in patients with hemophilia

Non-Hodgkin's lymphoma (NHL) is the most common human immunodeficiency virus (HIV)-associated malignancy in hemophiliacs. We studied the incidence and clinicopathologic features of NHL in 3,041 hemophiliacs followed at 18 US Hemophilia Centers between 1978 and 1989. Of the 1,295 (56.6%) who were HIV(+), 253 (19.5%) developed acquired immunodeficiency syndrome (AIDS), of whom 14 (5.5%) developed NHL. Three NHL occurred in HIV(-) hemophiliacs, for a 36.5-fold greater risk in HIV(+) than HIV(-) hemophiliacs (P < .001). The NHL incidence rate was 29-fold greater than in the US population by Surveillance, Epidemiology, and End Results (SEER) estimates (P < .001). Between 0 and 4 lymphomas have been observed per year between 1978 and 1989. At presentation 13 (92.9%) of the HIV(+) NHL were extranodal. Ten were stage IV, 1 stage II, and 3 stage IE. Ten (71.4%) were high-grade, 3 (21.4%) intermediate-grade, and 1 (7.1%) was a low-grade B-cell lymphoma. Epstein-Barr virus (EBV) DNA was detected in 36% by in situ hybridization, including one central nervous system (CNS) lymphoma. The mean CD4 cell count at NHL diagnosis was 64/mm3, the mean latency from initial HIV infection was estimated to be 59 months, and the median survival was 7 months. The incidence of basal cell carcinoma in HIV(+) hemophiliacs was 18.3-fold greater than in HIV(-) hemophiliacs (P < .001) and 11.4-fold greater than in the US population (P < .001). In conclusion, incidence rates of NHL and basal cell carcinoma in HIV(+) hemophiliacs are significantly increased over rates in HIV(-) hemophiliacs and over rates in the US population. Clinicopathologic presentation of NHL in HIV(+) hemophiliacs is similar to that in HIV(+) homosexual men.     

The affect of pH and bacterial phenotypic state on antibiotic efficacy

Antibiotics are routinely used in woundcare for the treatment of local and systemic infections. Our goals in this paper were to (i) evaluate the antibiotic sensitivity of bacteria isolated from burn and chronic wounds and (ii) evaluate the effect of pH and bacterial phenotype on the efficacy of antibiotics. Chronic and burn wound isolates, which had been routinely isolated from patients at West Virginia University Hospital, USA, were evaluated for their sensitivity to antibiotics. Antimicrobial susceptibility testing was performed using a standardised disk diffusion assay on agar (quasi/non biofilm) and poloxamer (biofilm). Many of the Gram-positive and -negative isolates demonstrated changes in susceptibility to antibiotics when grown at different pH values and phenotypic states. Findings of this study highlight the clinical relevance that both pH and the phenotypic state of bacteria have on antibiotic performance. The study in particular has shown that bacteria exhibit an enhanced tolerance to antibiotics when grown in the biofilm phenotypic state. Such a finding suggests that more appropriate antibiotic sensitivity testing for woundcare and medicine is warranted to help assist in the enhancement of positive clinical outcomes.