Ponesimod to treat multiple sclerosis

Ponesimod (ACT-128800) is a directly bioavailable, rapidly reversible sphingosine-1-phosphate (S1P) receptor modulator, highly selective for the subtype 1 (S1P1 receptor). It acts by blocking the egress of lymphocytes from the lymphoid organs, thus limiting the entry of autoreactive cells into the central nervous system. Unlike fingolimod, ponesimod does not require monitoring of the first dose, thanks to a 14-day uptitration regimen, which markedly reduces the incidence of cardiodynamic effects related to the initiation of therapy. Results from the OPTIMUM phase III trial demonstrated the superiority of ponesimod over teriflunomide on disease activity markers, without unexpected safety concerns. Furthermore, the drug is eliminated within 1 week of discontinuation, allowing for the reversibility of its effects. Ponesimod was recently approved in both the U.S. and E.U. for the treatment of relapsing forms of multiple sclerosis. This review summarizes the pharmacological characteristics of ponesimod and the main studies that led to its approval

Experimental assessment on exploiting low carbon ethanol fuel in a light-duty dual-fuel compression ignition engine

Compression ignition (CI) engines are widely used in modern society, but they are also recognized as a significative source of harmful and human hazard emissions such as particulate matter (PM) and nitrogen oxides (NOx). Moreover, the combustion of fossil fuels is related to the growing amount of greenhouse gas (GHG) emissions, such as carbon dioxide (CO2). Stringent emission regulatory programs, the transition to cleaner and more advanced powertrains and the use of lower carbon fuels are driving forces for the improvement of diesel engines in terms of overall efficiency and engine-out emissions. Ethanol, a light alcohol and lower carbon fuel, is a promising alternative fuel applicable in the dual-fuel (DF) combustion mode to mitigate CO2 and also engine-out PM emissions. In this context, this work aims to assess the maximum fuel substitution ratio (FSR) and the impact on CO2 and PM emissions of different nozzle holes number injectors, 7 and 9, in the DF operating mode. The analysis was conducted within engine working constraints and considered the influence on maximum FSR of calibration parameters, such as combustion phasing, rail pressure, injection pattern and exhaust gas recirculation (EGR). The experimental tests were carried out on a single-cylinder light-duty CI engine with ethanol introduced via port fuel injection (PFI) and direct injection of diesel in two operating points, 1500 and 2000 rpm and at 5 and 8 bar of brake mean effective pressure (BMEP), respectively. Noise and the coefficient of variation in indicated mean effective pressure (COVIMEP) limits have been chosen as practical constraints. In particular, the experimental analysis assesses for each parameter or their combination the highest ethanol fraction that can be injected. To discriminate the effect on ethanol fraction and the combustion process of each parameter, a one-at-a-time-factor approach was used. The results show that, in both operating points, the EGR reduces the maximum ethanol fraction injectable; nevertheless, the ethanol addition leads to outstanding improvement in terms of engine-out PM. The adoption of a 9 hole diesel injector, for lower load, allows reaching a higher fraction of ethanol in all test conditions with an improvement in combustion noise, on average 3 dBA, while near-zero PM emissions and a reduction can be noticed, on the average of 1 g/kWh, and CO2 compared with the fewer nozzle holes case. Increasing the load insensitivity to different holes number was observed

Advances in spinal cord imaging in multiple sclerosis

The spinal cord is frequently affected in multiple sclerosis (MS), causing motor, sensory and autonomic dysfunction. A number of pathological abnormalities, including demyelination and neuroaxonal loss, occur in the MS spinal cord and are studied in vivo with magnetic resonance imaging (MRI). The aim of this review is to summarise and discuss recent advances in spinal cord MRI. Advances in conventional spinal cord MRI include improved identification of MS lesions, recommended spinal cord MRI protocols, enhanced recognition of MRI lesion characteristics that allow MS to be distinguished from other myelopathies, evidence for the role of spinal cord lesions in predicting prognosis and monitoring disease course, and novel post-processing methods to obtain lesion probability maps. The rate of spinal cord atrophy is greater than that of brain atrophy (−1.78% versus −0.5% per year), and reflects neuroaxonal loss in an eloquent site of the central nervous system, suggesting that it can become an important outcome measure in clinical trials, especially in progressive MS. Recent developments allow the calculation of spinal cord atrophy from brain volumetric scans and evaluation of its progression over time with registration-based techniques. Fully automated analysis methods, including segmentation of grey matter and intramedullary lesions, will facilitate the use of spinal cord atrophy in trial designs and observational studies. Advances in quantitative imaging techniques to evaluate neuroaxonal integrity, myelin content, metabolic changes, and functional connectivity, have provided new insights into the mechanisms of damage in MS. Future directions of research and the possible impact of 7T scanners on spinal cord imaging will be discussed

Predictors of lymphocyte count recovery after dimethyl fumarate-induced lymphopenia in people with multiple sclerosis

Background: Dimethyl fumarate (DMF) is an oral drug approved for Relapsing Multiple Sclerosis (RMS) patients. Grade III lymphopenia is reported in 5–10% DMF-treated patients. Data on lymphocyte count (ALC) recovery after DMF withdrawal following prolonged lymphopenia are still scarce. Objectives: To characterize ALC recovery and to identify predictors of slower recovery after DMF interruption. Methods: Multicenter data from RMS patients who started DMF and developed lymphopenia during treatment were collected. In patients with grade II–III lymphopenia, ALCs were evaluated from DMF withdrawal until reaching lymphocyte counts > 800/mm3. Results: Among 1034 patients who started DMF, we found 198 (19.1%) patients with lymphopenia and 65 patients (6.3%) who discontinued DMF due to persistent grade II–III lymphopenia. Complete data were available for 51 patients. All patients recovered to ALC > 800 cells/mm3 with a median time of 3.4 months. Lower ALCs at DMF suspension (HR 0.98; p = 0.005), longer disease duration (HR 1.29; p = 0.014) and prior exposure to MS treatments (HR 0.03; p = 0.025) were found predictive of delayed ALC recovery. Conclusion: ALC recovery after DMF withdrawal is usually rapid, nevertheless it may require longer time in patients with lower ALC count at DMF interruption, longer disease duration and previous exposure to MS treatments, potentially leading to delayed initiation of a new therapy

Gemcitabine plus vinorelbine in advanced non-small cell lung cancer: a phase II study of three different doses

Our aim was to study the activity and toxicity of the gemcitabine plus vinorelbine (Gem Vin) combination and to identify the optimal dose. Previously untreated patients aged < 70 years, with stage IV or IIIb (not candidates for radiotherapy) non-small cell lung cancer were eligible. Studied dose-levels of Gem Vin, administered on days 1 and 8 every 3 weeks, were (mg m–2): level I = 1000/25; level II = 1200/25; level III = 1000/30; level IV = 1200/30. A feasibility study was performed at each dose-level, followed by a single-stage phase II study. Dose-level IV was unfeasible because of grade 4 neutropenia. Overall, out of 126 patients enrolled in phase II studies, there were one complete and 32 partial responses (response rate 26%: 95% CI 18–34%). Response rates were 27.9%, 21.4% and 29.3% at levels I, II and III, respectively. The treatment was well tolerated. Toxicity was less frequent and severe at level I. Overall median survival was 33 weeks (95% CI 28–40). Descriptive quality of life analysis showed that patients with a worse baseline global health status score tended to drop out of the study earlier than those with a better score. Gem Vin is feasible at different doses. It is sufficiently active and well tolerated. A phase III study to compare the effect on quality of life of Gem Vin (level I) vs cisplatin-based chemotherapy is ongoing. © 2000 Cancer Research Campaig

Mini-FLOTAC as an alternative, non-invasive diagnostic tool for Schistosoma mansoni and other trematode infections in wildlife reservoirs

Schistosomiasis and food-borne trematodiases are not only of major public health concern, but can also have profound implications for livestock production and wildlife conservation. The zoonotic, multi-host nature of many digenean trematodes is a significant challenge for disease control programmes in endemic areas. However, our understanding of the epidemiological role that animal reservoirs, particularly wild hosts, may play in the transmission of zoonotic trematodiases suffers a dearth of information, with few, if any, standardised, reliable diagnostic tests available. We combined qualitative and quantitative data derived from post-mortem examinations, coprological analyses using the Mini-FLOTAC technique, and molecular tools to assess parasite community composition and the validity of non-invasive methods to detect trematode infections in 89 wild Hubert’s multimammate mice (Mastomys huberti) from northern Senegal

Modulation of 5-fluorouracil as adjuvant systemic chemotherapy in colorectal cancer: the IGCS-COL multicentre, randomised, phase III study

The aims of this multicentre, randomised phase III trial were to evaluate: ( 1) the role of levamisol (LEV); and ( 2) the role of folinic acid ( FA), added to 5-fluorouracil (5FU) in the adjuvant treatment of colorectal cancer. Patients with histologically proven, radically resected stage II or III colon or rectal cancer were eligible. The study had a 2 x 2 factorial design with four treatment arms: ( a) 5FU alone, (b) 5FU+LEV, ( c) 5FU+FA, ( d) 5FU+LEV+FA, and two planned comparisons, testing the role of LEV and of FA, respectively. From March 1991, to September 1998, 1327 patients were randomised. None of the two comparisons resulted in a significant disease-free (DFS) or overall (OAS) survival advantage. The hazard ratio (HR) of relapse was 0.89 (95% confidence intervals (CI): 0.73 - 1.09) for patients receiving FA and 0.99 ( 95% CI 0.80 - 1.21) for those receiving LEV; corresponding HRs of death were 1.02 ( 95% CI: 0.80 - 1.30) and 0.94 ( 95% CI 0.73 - 1.20). Nonhaematological toxicity ( all grade vomiting, diarrhoea, mucositis, congiuntivitis, skin, fever and fatigue) was significantly worse with FA, while all other toxicities were similar. In the present trial, there was no evidence that the addition of FA or LEV significantly prolongs DFS and OAS of radically resected colorectal cancer patients