Effectiveness of Dimethyl Fumarate in Real-World Clinical Practice and Strategy to Minimize Adverse Effects and Use of Healthcare Resources.

BACKGROUND: Dimethyl fumarate (DMF) has shown efficacy in reducing relapse rates in patients with multiple sclerosis (MS). However, associated adverse effects (AE) such as gastrointestinal (GI) AE, flushing and lymphopenia are the main cause of treatment discontinuation. The aim of this study was to evaluate the effectiveness of DMF, and to assess strategies to reduce treatment discontinuation rates in routine clinical practice. PATIENTS AND METHODS: Ninety patients started DMF treatment between August 2015 and February 2020. Prior to DMF therapy, patients received written information regarding treatment and the management of AE, along with medical prescriptions. Clinical and analytical data were collected at clinical visits performed at least 6-monthly, and disease progression was evaluated by brain magnetic resonance imaging (MRI). RESULTS: Prior to DMF, 78.7% of patients had an annualized relapse rate (ARR) of 1.07 (range: 1-3) and median Expanded Disability Status Scale (EDSS) score of 1.0 (range: 0-2). At final follow-up, ARR and median EDSS scores were significantly reduced to 0.09 (range: 0-2; p< 0.001) and 0 (range: 0-1.625; p< 0.001), respectively. Just over one quarter of patients with brain MRI (26.8% of 71 patients) showed improvement in disease activity based on MRI evaluation. Lymphopenia was associated with previous treatment lines (p=0.042) and longer disease duration (p=0.032). A total of twelve patients abandoned DMF treatment, mainly due to lymphopenia (7.9%), but none did it because of GI AE or flushing. CONCLUSION: In our series, DMF showed high clinical and radiological efficacy. Providing patients with complete information prior to treatment on the management of associated AE helps them to better understand what to expect, improves tolerance and reduces clinical and telephone consultations, which may help to reduce the use and cost of healthcare resources.

Long-term effectiveness of glatiramer acetate in clinical practice conditions.

Glatiramer acetate currently represents one of the main treatments for relapsing-remitting multiple sclerosis (RRMS). However, the information available about its long-term effect in clinical practice is still limited. Thus, this multicenter retrospective cohort study aimed to assess the long-term effectiveness of glatiramer acetate in this setting. The study population included RRMS patients treated with glatiramer acetate for at least 5 years after its marketing authorization and the primary endpoint was long-term clinical effectiveness, defined as absence of disability progression for at least five consecutive years. A total of 149 patients were included into the study, who had received glatiramer acetate for a mean of 6.9 ± 1.4 years (5 years, n=149; 6 years, n=112; 7 years, n=63; 8 years, n=32; 9 years, n=21). More than 85% of patients remained free from disability progression through years 1 to 9 of glatiramer acetate treatment, and 75.2% showed absence of disability progression for at least five consecutive years. Expanded Disability Status Scale (EDSS) scores were maintained, with most patients showing stable/improved EDSS and 92.6% sustaining EDSS <6. Decreased annual relapse rates and increased proportion of relapse-free patients were maintained during the whole glatiramer acetate treatment compared to the year prior to its authorization (p<0.001). The number of gadolinium-enhanced T1-weighted lesions also decreased from pre-glatiramer-acetate assessment to last follow-up whilst on glatiramer acetate (p<0.05). In conclusion, administration of glatiramer acetate shows long-term clinical effectiveness for RRMS treatment; its effect under clinical practice conditions slowed disability progression and reduced relapse occurrence for up to 9 years.

Effects of (-)-nicotine and (-)-cotinine on 6-hydroxydopamine-induced oxidative stress and neurotoxicity: relevance for Parkinson's disease.

In view of the apparent controversial properties of (-)-nicotine (NIC) in relation to both oxidative stress and neuroprotection, we studied the effects of NIC on hydroxyl radical (*OH) formation, oxidative stress production by 6-hydroxydopamine (6-OHDA) autoxidation in the presence and absence of ascorbate, and 6-OHDA neurotoxicity. Both NIC and (-)-cotinine (COT) exhibited increased *OH production during 6-OHDA autoxidation. Although the same effect was observed in *OH generation by the Fenton reaction (H2O2 + Fe2+), this reaction was completely prevented with the previous incubation of Fe2+ with NIC or COT. Furthermore, both NIC and COT demonstrated a capacity to be able to reduce the TBARS formation provoked in rat brain mitochondrial preparations by 6-OHDA autoxidation. This effect is assumed as a consequence of the action of NIC and COT on lipid peroxidation propagation. We treated with NIC (1mg/kg, i.p.) two 6-OHDA-induced rat models of Parkinson's disease. However, only in one of these models did we obtain clear evidence of a neuroprotective effect of NIC on nigrostriatal terminals, as revealed by immunohistochemistry against tyrosine hydroxylase. Thus, the antioxidant properties of both NIC and COT in relation to the lipid peroxidation induced by 6-OHDA autoxidation, together with their reported capacity to prevent the Fenton reaction, probably by sequestration of Fe2+, may contribute to an understanding of its neuroprotective properties. In addition, the reported capacity of both NIC and COT to increase the production of *OH by 6-OHDA autoxidation might help explain the controversial observation found under different experimental conditions.

Effects of aluminum and zinc on the oxidative stress caused by 6-hydroxydopamine autoxidation: relevance for the pathogenesis of Parkinson's disease.

Aluminum and zinc have been related to the pathogenesis of Parkinson's disease (PD), the former for its neurotoxicity and the latter for its apparent antioxidant properties. 6-Hydroxydopamine (6-OHDA) is an important neurotoxin putatively involved in the pathogenesis of PD, its neurotoxicity often being related to oxidative stress. The potential effect of these metals on the oxidative stress induced by 6-OHDA autoxidation and the potential of ascorbic acid (AA), cysteine, and glutathione to modify this effect were investigated. Both metals, particularly Al3+, induced a significant reduction in *OH production by 6-OHDA autoxidation. The combined action of AA and a metal caused a significant and sustained increase in *OH generation, particularly with Al3+, while the effect of sulfhydryl reductants was limited to only the first few minutes of the reaction. However, both Al3+ and Zn2+ provoked a decrease in the lipid peroxidation induced by 6-OHDA autoxidation using mitochondrial preparations from rat brain, assessed by TBARS formation. In the presence of AA, only Al3+ induced a significant reduction in lipid peroxidation. After intrastriatal injections of 6-OHDA in rats, tyrosine hydroxylase immunohistochemistry revealed that Al3+ reduces 6-OHDA-induced dopaminergic lesion in the striatum, which corroborates the involvement of lipid peroxidation in 6-OHDA neurotoxicity and appears to discard the participation of this mechanism on PD by Al3+ accumulation. The previously reported antioxidant properties of Zn2+ appear to be related to the induction of Zn2+-containing proteins and not to the metal per se.