Effect of combined IFNbeta-1a and glatiramer acetate therapy on GA-specific T-cell responses in multiple sclerosis.

The combined treatment with interferon beta (IFNbeta) and glatiramer acetate (GA) is of current interest in multiple sclerosis (MS). The therapeutic effect of GA in MS is believed to be mediated by GA-specific Th2 cells. IFNbeta has a significant anti-proliferative effect on GA-induced lymphoproliferation in vitro. Therefore, we examined the possibility that IFNbeta may interfere with the generation and phenotype of GA T-cell responses in MS patients receiving combined therapy. Sixty-six GA-specific T-cell lines (TCL) were generated ex vivo from five MS patients enrolled in an open-label dinical trial of combined IFNbeta/GA treatment. Controls included 83 pretreatment and 131 on-treatment GA-TCL from 11 MS patients treated with GA only, and five GA-TCL generated from four patients receiving IFNbeta-1a monotherapy. IFNgamma and IL-5 (markers of Th1 and Th2 responses, respectively) were assayed by ELISA in GA-TCL supematants. Th1/Th2 bias was defined by the IFNgamma/IL-5 level ratio ( >2 = Th1 bias, <0.5 = Th2 bias, and 0.5-2 = Th0 bias). The frequency with which GA-reactive TCL were generated was 37.0% for the patients in the combination trial compared to 33.3% in the patients receiving GA alone. The mean stimulation index of the GA-TCL was 8.41 (range 2-42) for the combination compared to a mean of 6.29 (range 2-37) for the GA-treated group--a nonsignificant difference. Mean GA-TCL IFNgamma production was significantly lower in all treatment groups compared to pretreatment IL-5 levels were enhanced in all treatment groups compared to pretreatment levels, but the change was not statistically significant. The Th1/Th0/Th2 distribution of GA-TCL was 7%/30%/63% for the GA+IFNbeta group, 8%/9%/83% for the GA group, compared to 48%/21%/31% pre-GA treatment. All five GA-TCL from the IFNbeta-1a monotherapy patients were Th2-biased. We conclude that IFNbeta-1a does not affect the generation of GA-reactive T cells in vivo. Although more Th0 G4-TCL occurred with combination therapy than with G4 treatment alone, both groups shared an overall Th2 bias. Therefore, we speculate that combined therapy is unlikely to reduce the efficacy of GA treatment in MS.

Fatigue in multiple sclerosis and its relationship to depression and neurologic disability.

We studied multiple sclerosis fatigue (MSF) and its relationship to depression and disability. Seventy-one patients [50 relapsing-remitting, 21 secondary progressive] were grouped by Fatigue Severity Scale (FSS) into MS-fatigue (MSF) (FSS>/=5; n=46) or MS-nonfatigue (MSNF) (FSS

Fatigue in multiple sclerosis: cross-sectional correlation with brain MRI findings in 71 patients.

Fatigue is an unexplained but common and disabling symptom in MS. We assessed fatigue in 71 patients with MS and identified MS-fatigue (MSF) and MS-nonfatigue (MSNF) groups. Fatigue severity did not correlate with regional or global MRI plaque load or atrophy assessed by conventional sequences. No significant differences were noted in any MRI measures between MSF and MSNF groups. We suggest that brain MRI disease topography or severity does not explain fatigue in MS and that fatigue is likely due to mechanisms poorly characterized by conventional MRI.

Environmental hazard assessment of pharmaceuticals.

The pharmaceuticals and pharmaceutical metabolites salicylic acid, paracetamol, clofibrinic acid, and methotrexate were examined with regard to their biological degradability and toxicity toward algae, Daphnia, fish embryos, luminescent bacteria, ciliates, and the fish cell line BF-2. The EC50 values calculated for the most sensitive organismic test (all except cell cultures) in each case were for salicylic acid, 37 mg/L (fish embryos); for paracetamol, 50 mg/L (Daphnia); for clofibrinic acid, 86 mg/L (fish embryos); and for methotrexate, 45 mg/L (ciliates). However, in the case of paracetamol, clofibrinic acid, and methotrexate, the fish cell line BF-2 reacted even more sensitively with EC50 values of 19 mg/L (paracetamol), 14 mg/L (clofibrinic acid), and 3 mg/L (methotrexate). Salicylic acid and paracetamol proved to be easily degradable. The predicted exposure concentration calculated according to the procedure of the EU Draft Phase I for new pharmaceuticals (CEC III/5504/94, draft 4) was based on the total estimated quantity of these substances consumed and indicated that their entry into the environment is theoretically possible. These results show that (1) the four tested pharmaceuticals may be present in the environment, (2) the substances led to effects in at least one ecotoxicological test, and (3) the most sensitive reactions were observed for a nonstandard test which incorporates relevant end points for the respective pharmaceuticals. This demonstrates that a limitation to the standard tests (algae, Daphnia, and fish) would have underestimated the toxicity of paracetamol, clofibrinic acid, and methotrexate. In addition to improved exposure estimates, the EU guideline should therefore contain a test strategy adapted to their modes of action, which permits the definite identification of pharmaceuticals with high ecotoxic potential, and consequently the appropriate provisions.