Comparative analysis of first-year fingolimod and natalizumab drug discontinuation among Swedish patients with multiple sclerosis.

BACKGROUND: Natalizumab (NTZ) and fingolimod (FGL) are mainly used second line in relapsing-remitting multiple sclerosis (MS), although pivotal trials included mainly treatment-naïve patients. OBJECTIVE: This study aims to provide real-world data on safety and discontinuation rates. METHODS: Using IMSE, a drug monitoring registry for all newer MS drugs in Sweden, we analysed differences in baseline characteristics and 1-year drug survival for patients registered 2011-2013, initiating treatment with NTZ (n=640) or FGL (n=876). Among FGL initiators, n=383 (44%) had previously used NTZ (FGL(afterNTZ)). RESULTS: Compared with NTZ, the FGL cohort was older and more often male (36/38 years, 24%/33% males). Baseline Expanded Disability Status Scale was similar across groups, but MS Severity Score was higher in NTZ patients, and Symbol Digit Modalities Test and MS Impact Scale (MSIS-29) was higher in FGL(afterNTZ) versus FGL(NTZ-naïve) patients. Proportion on drug after 1 year was high, NTZ=87%, FGL(NTZ-naïve)=83% and FGL(afterNTZ)=76%. Adverse events was the most frequent reason for discontinuing FGL (FGL(NTZ-naïve)=9%, FGL(afterNTZ)=12%), and was significantly higher than on NTZ (3%). In contrast, the proportion of patients stopping treatment due to lack of effect was more similar: NTZ=4%, FGL(NTZ-naïve)=3%, FGL(afterNTZ)=8%. CONCLUSION: FGL and NTZ were both well tolerated, but FGL less so than NTZ, especially in patients switching to FGL from NTZ. Group differences were not explained by differences in recorded baseline characteristics.

Clonidine prolongs fentanyl-induced ventilatory depression.

The aim of the present study was to investigate the effect of intravenously (i.v.) administered fentanyl and clonidine on ventilation in 12 healthy male volunteers (age 30.8 +/- 4.9 years) who either received fentanyl alone (1.5 > or = micrograms kg-1) or fentanyl (1.5 > or = micrograms kg-1) in combination with clonidine (3 > or = micrograms kg-1). The effect on ventilation was measured with a CO2 rebreathing system. The respiratory depression caused by fentanyl disappeared 120 min after injection. The corresponding slopes were 7430 +/- 2075 mL kPa-1 prior to (t0) and 6263 +/- 1864 mL kPa-1 120 min post-application (base-line vs. t120; P = 0.106). An impaired ventilatory response was observed during CO2 rebreathing at t120 after the injection of fentanyl and clonidine. Before drug administration, the slope of the response curves was 7700 +/- 2800 mL kPa-1, which was reduced to 5480 +/- 2135 mL kPa-1 (P < 0.035) at t120. These data suggest a prolongation of a fentanyl-induced ventilatory depression when used in combination with clonidine.

[Prolongation of fentanyl-induced decreased arousal by clonidine]. / Untersuchungen zur Verlängerung einer fentanylinduzierten Vigilanzminderung durch Clonidin.

Both fentanyl and clonidine lead to a reduction of vigilance. We tested the influence of clonidine on a fentanyl induced change of vigilance using a cross-out concentration test (b-cross-out test). With local ethics committee approval, we conducted a randomised double-blinded cross-over study with 10 healthy male subjects (25-35 years old). Each volunteer received intravenously at two separate sessions 1.5 micrograms/kg fentanyl and 1.5 micrograms/kg fentanyl plus 3 micrograms/kg clonidine. For testing the level of vigilance a concentration test (b-cross-out) was used. The number of correctly revised marks was evaluated prior to drug administration (TI), directly after application, one hour later and two hours later. Our data underwent a multiple analysis of variance. With fentanyl two hours after application the mean increase of correctly revised marks was 12% when compared to those prior to application (p < 0.024). This means that with fentanyl a learning effect was achieved as described in the literature. With fentanyl and clonidine two hours after application, a decrease in vigilance of 7 1/4 in comparison with TI was seen (n.s.). This reduction of vigilance should be considered during the postoperative course and especially with regard to ambulant anaesthesia when using clonidine.