Niemann-Pick Type C1 (NPC1) is an autosomal recessive inherited disorder characterized by accumulation of cholesterol and glycosphingolipids. Previously, we demonstrated that BALB/c-npc1nihNpc1−/− mice treated with miglustat, cyclodextrin and allopregnanolone generally performed better than untreated Npc1−/− animals. Unexpectedly, they also seemed to accomplish motor tests better than their sham-treated wild-type littermates. However, combination-treated mutant mice displayed worse cognition performance compared to sham-treated ones. To evaluate effects of these drugs in healthy BALB/c mice, we here analyzed pharmacologic effects on motor and cognitive behavior of wild-type mice. For combination treatment mice were injected with allopregnanolone/cyclodextrin weekly, starting at P7. Miglustat injections were performed daily from P10 till P23. Starting at P23, miglustat was embedded in the chow. Other mice were treated with miglustat only, or sham-treated. The battery of behavioral tests consisted of accelerod, Morris water maze, elevated plus maze, open field and hot-plate tests. Motor capabilities and spontaneous motor behavior were unaltered in both drug-treated groups. Miglustat-treated wild-type mice displayed impaired spatial learning compared to sham- and combination-treated mice. Both combination- and miglustat-treated mice showed enhanced anxiety in the elevated plus maze compared to sham-treated mice. Additionally, combination treatment as well as miglustat alone significantly reduced brain weight, whereas only combination treatment reduced body weight significantly. Our results suggest that allopregnanolone/cyclodextrin ameliorate most side effects of miglustat in wild-type mice.

No abstract

Purpose This study aimed to assess 5-year effectiveness and safety of femoropopliteal angioplasty with the Luminor® 35 drug-coated balloon (DCB). Materials and Methods The EffPac trial was a prospective, multicenter, randomized controlled trial that enrolled 171 patients of Rutherford category 2 to 4 with medium length femoropopliteal lesions. Patients were allocated 1:1 to either Luminor® 35 DCB angioplasty or plain old balloon angioplasty (POBA). Assessment at 5 years included primary patency, freedom from clinically driven target lesion revascularization (CD-TLR), clinical improvement, and target limb amputation. Long-term vital status was ascertained in 97.1% of the participants. Results Kaplan–Meier curves at 5 years demonstrate a primary patency of 61.4% after DCB angioplasty and 53.5% after POBA (log-rank p = 0.040) with a decreasing difference throughout the observation period. Freedom from TLR was 82.1% and 73.7%, respectively (log-rank p = 0.050). Incidence of primary clinical improvement was similar between groups (61% DCB vs. 64% POBA, p = 0.94). Major target limb amputation was necessary in one POBA-group participant. Freedom from all-cause death at 5 years was 88.5% after DCB and 86.0% after POBA (log-rank p = 0.34). Conclusions Primary patency after femoropopliteal DCB angioplasty remained superior to POBA throughout 5 years, however, with decreasing difference. Clinical improvement, freedom from TLR, and all-cause mortality were similar between groups over the long term. (Effectiveness of Paclitaxel-Coated Luminor® Balloon Catheter Versus Uncoated Balloon Catheter in the Superficial Femoral Artery [EffPac]; NCT02540018).

Aims: Although paclitaxel drug-coated balloon (DCB) angioplasty is an established endovascular treatment for peripheral artery disease, restenosis remains a major concern. Thus, we compared a novel paclitaxelcoated DCB with nano-coating technology with uncoated plain old balloon angioplasty (POBA).Methods and results: This multicentre trial randomly assigned 171 patients with stenotic and occlusive lesions of the femoropopliteal artery to angioplasty with a novel DCB or uncoated POBA. The primary endpoint, late lumen loss at six months, was 0.92 mm lower in the DCB group (95% CI: −1.36 to −0.49 mm, p<0.001). Patients showed improved walking after DCB treatment at six months (p=0.021). In the DCB group, 44.6% and 50% of the patients improved by three Rutherford-Becker classification stages after six to 12 months, respectively (POBA: 27.8% and 36.8%, respectively). Only one patient needed TLR (1.3%) in the DCB group, compared to 14 patients (18.7%) in the POBA group after 12 months (relative risk [RR]=0.08, 95% CI: 0.01-0.53, p<0.001). Primary patency was 90.3% (DCB group) versus 65.3% (POBA group) after 12 months (RR=1.38, 95% CI: 1.14-1.67, p<0.001). Conclusions:The novel DCB was effective and safe for inhibiting restenosis. Moreover, it demonstrated a better improvement in walking than POBA and showed no mortality concerns due to paclitaxel application after 12 months. Clinical Trials Identifier: NCT02540018

Abstractω3‐polyunsaturated free fatty acids (ω3‐PUFAs), particularly docosahexaenoic (DHA) and eicosapentaenoic acid (EPA), are thought to exert health promoting effects in metabolic and in inflammatory diseases. The molecular mechanisms of these beneficial effects are only partially understood. DHA and EPA activate Free Fatty Acid receptor 4 (GPR120/FFA4). Recently, the first orally available, synthetic ligand of FFA4, 3‐[2‐chloro‐5‐(trifluoromethoxy)phenyl]‐3‐azaspiro[5.5]undecane‐9‐acetic acid (“compound A”; cpd A) has been developed. Cpd A exhibits distinctly higher potency, efficiency, and selectivity at FFA4 than ω3‐PUFAs and ameliorates insulin resistance and adipose tissue inflammation in the mouse. With GPR120/FFA4 activation believed to also attenuate tissue inflammation in autoimmune diseases, cpd A may also have a beneficial effect in these diseases. We have therefore addressed the therapeutic potential of cpd A in mouse models of three prototypical autoimmune diseases, specifically psoriasis, rheumatoid arthritis, and bullous pemphigoid. The effect of cpd A on the course of Aldara™‐induced psoriasis‐like dermatitis, K/BxN serum transfer arthritis, and antibody transfer pemphigoid disease‐like dermatitis was scrutinized. Cpd A did not alter the course of Aldara‐induced psoriasis‐like dermatitis, K/BxN serum transfer arthritis, or antibody transfer pemphigoid disease‐like dermatitis. Our results suggest that therapeutic regimens solely relying on FFA4 activation do not bear the potential to treat inflammatory diseases. With cpd A distinctly more potent in activating GPR120/FFA4 than ω3‐PUFAs, this also suggests that GPR120/FFA4 activation by ω3‐PUFAs does not significantly contribute to the health‐promoting effects of ω3‐PUFAs in autoimmune diseases.