Risk of fingolimod rebound after switching to cladribine or rituximab in multiple sclerosis.

BACKGROUND: A sudden onset of extensive disease activity, including severe clinical relapse and extensive brain or spinal magnetic resonance imaging (MRI) lesions, termed "rebound" disease activity has been reported after withdrawal of fingolimod in patients with multiple sclerosis (MS). OBJECTIVE: To compare the risk of rebound after switching from fingolimod to cladribine or rituximab in MS. METHODS: All patients switching from fingolimod to cladribine or rituximab were included in a retrospective cohort study utilizing prospectively collected data from two university hospitals with different treatment strategies. RESULTS: A total of 73 patients with at least 6 months follow-up after switching were identified, 33 patients had switched from fingolimod to cladribine and 40 patients to rituximab. No patients in the rituximab group and seven (21.1%) in the cladribine group qualified for rebound disease activity. Ten (30.3%) of the patients using cladribine and five (12.5%) of the patients using rituximab experienced a relapse. MRI disease activity was seen in 18 (54.5%) and eight (20.0%) of the patients using cladribine and rituximab, respectively. Younger age and previous high relapse rate were associated with increased risk of rebound in the cladribine group. CONCLUSIONS: We identify a lower risk of rebound during the first year after switching from fingolimod to rituximab compared to cladribine, indicating a better initial clinical outcome with the former treatment strategy.

Synthesis of racemic ß-chamigrene, a spiro[5.5]undecane sesquiterpene [corrected].

The present paper describes a total synthesis of racemic ß-chamigrene, a sesquiterpene with a spiro[5.5]undecane carbon framework. Compared with previously reported ß-chamigrene syntheses, we were able to reduce the total number of reaction steps, which also resulted in a significant improvement of the overall yield. The commercially available ketone 6-methylhept-5-en-2-one was transformed by known simple procedures into 3,3-dimethyl-2-methylenecyclohexanone. This reacted with isoprene by a Diels-Alder reaction to give a spiro ketone. An olefination reaction on this compound gave the target molecule.

Synthesis of All-Z-1,6,9,12,15-octadecapenten-3-one, a vinyl ketone polyunsaturated marine natural product isolated from Callysponga sp.

The synthesis of the marine natural product 1,6Z,9Z,12Z,15Z-octadecapentaen-3-one (1) has been achieved by two different routes starting from the ethyl esters of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), respectively. Using EPA ethyl ester as starting material the polyunsaturated vinyl ketone lipid 1 was obtained in 17% overall yield.

Enantiopure dihalocyclopropyl alcohols and esters by lipase catalyzed kinetic resolution.

Four halogenated cyclopropane derivatives with a side chain containing a primary (1 and 2) or secondary (3 and 4) alcohol moiety were subject to kinetic resolution catalyzed by lipases. Two of them containing secondary alcohol groups gave excellent results with Candida antarctica lipase B with E-values around 1000. Two enantiopure alcohols and two enantiopure butanoates are described: (1S,1'S)-1-(2',2'-dichloro-3',3'-dimethylcyclopropyl) ethanol (3), the corresponding (1R,1'R)-butanoate (3b) and (1S,1'S)-1-(1'-methyl-2',2'-dibromocyclopropyl) ethanol (4) and the corresponding (1R,1'R)-butanoate (4b).

The infrared and Raman spectra of trans- and cis-tetrachloro-tetramethylbicyclopropylidene.

The title compounds trans- and cis-2,2,2',2'-tetrachloro-3,3,3',3'-tetramethyl-bicyclopopylidene were synthesized, and their infrared and Raman spectra were recorded. Non-coincidence between the IR and Raman bands of the trans compound suggested C(2h) symmetry and a planar ring system. In the cis compound most of the IR and Raman bands coincided and a C(2v) symmetry seems likely. The exocyclic CC double bond gave rise to a medium/weak Raman band at 1,847 cm(-1) in the trans compound. In the cis derivative IR and Raman bands both at 1,825 cm(-1) were observed. From similarities with related molecules, the ring breathing, the antisymmetric ring stretch, the CCl(2) out-of-phase and in-phase stretch and the out-of-plane ring bending modes have been tentatively assigned for the trans and cis compounds.

The antifouling activity of some juvenoids on three species of acorn barnacle, Balanus.

Analogues of insect juvenile hormones (juvenoids) have been tested for settling inhibition of cyprids from three species of barnacle, Balanus balanoides (L.), Balanus improvisus Darwin and Balanus amphitrite Darwin. Some 3-alkoxypyridine derivatives exhibited strong activity at mg litre(-1) concentrations; 3,7-dimethyloctyl 2-methyl-5-pyridyl ether (8) gave an EC(50) of 0.006 mg litre(-1) when tested on B. balanoides. When compound 8 and similar juvenoids were incorporated into paints, test panels kept in seawater for 8 months were free of barnacles.

Sulfur-substituted and alpha-methylated fatty acids as peroxisome proliferator-activated receptor activators.

FA with varying chain lengths and an alpha-methyl group and/or a sulfur in the beta-position were tested as peroxisome proliferator-activated receptor (PPAR)alpha, -delta(beta), and -gamma ligands by transient transfection in COS-1 cells using chimeric receptor expression plasmids, containing cDNAs encoding the ligand-binding domain of PPARalpha, -delta, and -gamma. For PPARalpha, an increasing activation was found with increasing chain length of the sulfur-substituted FA up to C14-S acetic acid (tetradecylthioacetic acid = TTA). The derivatives were poor, and nonsignificant, activators of PPARdelta. For PPARgamma, activation increased with increasing chain length up to C16-S acetic acid. A methyl group was introduced in the alpha-position of palmitic acid, TTA, EPA, DHA, cis9,trans11 CLA, and trans10,cis12 CLA. An increased activation of PPARalpha was obtained for the alpha-methyl derivatives compared with the unmethylated FA. This increase also resulted in increased expression of the two PPARalpha target genes acyl-CoA oxidase and liver FA-binding protein for alpha-methyl TTA, alpha-methyl EPA, and alpha-methyl DHA. Decreased or altered metabolism of these derivatives in the cells cannot be excluded. In conclusion, saturated FA with sulfur in the beta-position and increasing carbon chain length from C9-S acetic acid to C14-S acetic acid have increasing effects as activators of PPARalpha and -gamma in transfection assays. Furthermore, alpha-methyl FA derivatives of a saturated natural FA (palmitic acid), a sulfur-substituted FA (TTA), and PUFA (EPA, DHA, c9,t11 CLA, and t10,c12 CLA) are stronger PPARalpha activators than the unmethylated compounds.

Insect juvenile hormone analogues and their biological activity on sea lice (Lepeophtheirus salmonis).

A number of synthetic compounds that exhibit juvenile hormone activity when tested on the insect species Tenebrio molitor have been shown to inhibit the development of the sea lice species Lepeophtheirus salmonis. The testing was carried out on both isolated nauplius larvae and live Atlantic salmon (Salmo salar).

Studies on the synthesis and biological properties of non-carrier-added [(125)I and (131)I]-labeled arylalkylidenebisphosphonates: potent bone-seekers for diagnosis and therapy of malignant osseous lesions.

Arylalkylidenebisphosphonates labeled with nca [(125)I or (131)I] have been synthesized and their biological function investigated. The label was attached to the aromatic group in high yield and under mild conditions by means of iododesilylation. The bone affinities of the radioactive compounds were investigated in normal Balb/C mice. The compound 1-hydroxy(m-iodo[(125,131)I]-phenylethylidene)-1,1-bisphosphonate was found to possess superior bone affinity compared to others, and its in vivo deiodination was insignificant. The uptake in femur 24h after injection was 850 +/- 265% and 986 +/- 118% of injected dose per gram tissue times gram body weight in mice and rats, respectively. The therapeutic potential of the compound was investigated in two tumor models in athymic (nude) rats, one model for mixed lytic/sclerotic metastatic bone-lesions originating from breast cancer and the other model simulating osseous osteosarcoma. The effects in these models compare favorably to those observed for established treatment modalities. The experiments demonstrate that radioiodinated bisphosphonates may have a potential for diagnosis and therapy of malignant osseous lesions.