Neurological update: treatment escalation in multiple sclerosis patients refractory to fingolimod—potentials and risks of subsequent highly active agents

A critical issue in the management of relapsing MS (RMS) is the discontinuation of disease-modifying treatments (DMT) due to lack of efficacy, intolerability or impending risks. With new therapeutic agents introduced into the treatment of RMS, immediate- and long-term consequences of sequential drug use, as well as the effect of the sequence in which the drugs are given, are unclear but may affect efficacy, adverse events, and long-term immunocompetence. In the absence of clinical studies specifically addressing these concerns, observations from clinical practice are of particular value in guiding current management algorithms. Prompted by a study published by Ferraro et al. in this journal, we set out to provide an overview of the published real-world evidence on the effectiveness and safety of switching from fingolimod to another DMT in patients with active RMS. Seventeen publications reporting relevant information were identified. The literature suggests that immune cell depletion induced by alemtuzumab or ocrelizumab is associated with an increased risk of relapse and worsening disability in patients switching from fingolimod compared to patients switching from other therapeutic agents. However, the evidence reported for natalizumab and cladribine is inconclusive. While shortening of the washout period may limit early disease reactivation after fingolimod discontinuation, there is no strong evidence that the duration of the washout period or the absolute lymphocyte count at baseline are predictors of attenuated long-term efficacy. Further real-world studies are required to better understand outcomes among patients who are under-represented in controlled trials.

Anxiolytic Effect and Improved Sleep Quality in Individuals Taking Lippia citriodora Extract

The current fast-moving, hectic lifestyle has increased the number of individuals worldwide with difficulties in managing stress, which in turn is also affecting their sleep quality. Therefore, the objective of the current study was to assess a natural plant-based dietary supplement comprised of lemon verbena (Lippia citriodora) extract, purified in phenylpropanoids, in alleviating stress and improving quality of sleep. A double-blind, placebo-controlled study was conducted for 8 weeks, followed by a 4-week washout period. Both validated questionnaires and functional tests were performed during the study, whereas questionnaires were used after the washout. As a result, the group taking the lemon verbena extract significantly reduced their perception of stress after 8 weeks, which was corroborated by a significant decrease in cortisol levels. After the washout period, the subjects reported to present even lower stress levels, due to the lasting effect of the ingredient. As for sleep quality, the subjects taking the supplement reported feeling better rested, with a stronger effect observed in women. Sleep tracking using a wearable device revealed that the supplement users improved their times in the deeper stages of sleep, specifically their percentage of time in deep sleep and REM. In conclusion, lemon verbena extract purified in phenylpropanoids is revealed as a natural solution to help individuals to improve their stress and sleep quality.

Limits of cross-modal plasticity? Short-term visual deprivation does not enhance cardiac interoception, thermosensation, or tactile spatial acuity

In the present study, we investigated the effect of short-term visual deprivation on discriminative touch, cardiac interoception, and thermosensation by asking 64 healthy volunteers to perform four behavioral tasks. The experimental group contained 32 subjects who were blindfolded and kept in complete darkness for 110 minutes, while the control group consisted of 32 volunteers who were not blindfolded but were otherwise kept under identical experimental conditions. Both groups performed the required tasks three times: before and directly after deprivation (or control) and after an additional washout period of 40 minutes, in which all participants were exposed to normal light conditions. Our results showed that short-term visual deprivation had no effect on any of the senses tested. This finding suggests that short-term visual deprivation does not modulate basic bodily senses and extends this principle beyond tactile processing to the interoceptive modalities of cardiac and thermal sensations.

Prolonged Washout Period for Avoiding Azilsartan-Induced Refractory Hypotension During General Anesthesia for a Patient With Renal Impairment

Angiotensin receptor blockers (ARBs) are widely used to treat hypertension, but severe refractory hypotension during general anesthesia is a well-known complication associated with the continuation of ARBs during the perioperative period. It has therefore been recommended that ARBs be withheld for 24 hours before induction of general anesthesia. However, impaired renal function affects the pharmacokinetics of each ARB differently. The half-life of azilsartan is prolonged in accordance with the degree of renal impairment. Herein, we describe a patient with chronic kidney disease grade 3B who experienced severe refractory hypotension after induction of general anesthesia requiring administration of dopamine following inadequate responses to ephedrine and phenylephrine despite a 24-hour azilsartan washout period. When the same patient underwent general anesthesia for a subsequent surgery, azilsartan was withheld for 48 hours before induction, resulting in mild intraoperative hypotension that responded adequately to phenylephrine. Severe refractory hypotension during general anesthesia cannot always be avoided by holding azilsartan for 24 hours in patients with significant renal impairment. Therefore, a longer washout period may be preferable for patients regularly taking azilsartan who also have concurrent substantial renal impairment.

Empleo de semillas como ingrediente saciante: chía y sésamo

Debido al gran aumento de la prevalencia del sobrepeso y obesidad en todo el mundo, ha aumentado el inte- rés de estudio de los mecanismos que llevan a la población a un desequilibrio energético, aumentando su peso corporal de forma excesiva. El control de la ingesta de energía va determinado por la percepción de la saciedad durante y después de las comidas. Hay ciertos alimentos que por sus características nutricionales (cantidad de fibra, hidratos de carbono, proteína y grasa) pueden influenciar de forma positiva sobre el apetito (disminuyen- do el deseo por la comida). Por ello sería una buena estrategia nutricional ver cuáles de los alimentos presenta mayor relación sobre la saciedad. Realizamos un ensayo clínico cruzado aleatorizado con un periodo de lavado de 5 días, como mínimo. El objetivo del presente estudio fue evaluar el efecto de las semillas de sésamo y chía (por su gran cantidad de fibra soluble) sobre la saciedad (introducidas junto con yogur en el desayuno). La muestra estaba formada por 18 voluntarios. Cada voluntario realizó los 3 tipos de desayunos de forma aleatoria: (café con leche o té con leche + tostada con aceite de oliva y sal) + (yogur, yogur con chía o yogur con sésamo). Antes del desayuno tuvieron que rellenar una encuesta sobre apetito (VAS) y después 7 más (a los 15, 45, 75, 105, 135, 165 y 195 minutos tras el desayuno). Para valorar el efecto saciante de las semillas, se analizaron las preguntas del VAS que presentan relación directa con la saciedad, y se realizó un ANOVA. Los resultados mos- traron que no había diferencias estadísticamente significativas (p>0.05) entre las semillas estudiadas. Nowadays, there is a high prevalence of overweight and obesity around the world, so the inter- est in studying the mechanisms that lead the population to an energy imbalance has increased. The control of energy intake is determined by the perception of satiety during and after meals. There are certain foods that, due to their nutritional characteristics (amount of fibre, carbohydrates, protein and fat), can positively influence the appetite (decreasing the desire to eat). Thus, it would be a good nutritional strategy to see which foods have a greater satiety effect. We performed a randomi- zed crossover clinical trial with at least 5-days washout period. The objective of the present study was to evaluate the effect of sesame and chia seeds (due to their large amount of soluble fibre) on satiety. The sample consisted of 18 volunteers. Each one performed the 3 types of breakfasts randomized: (coffee with milk or tea with milk + toast with olive oil and salt) + (yoghurt, yoghurt with chia or yoghurt with sesame). Before breakfast they had to fill out an appetite survey (VAS) and then 7 more (at 15, 45, 75, 105, 135, 165 and 195 min after breakfast). To assess the satiating effect of the seeds, the questions of the VAS directly related to satiety were analysed, and ANOVA was performed. The results showed that there were no statistically significant differences (p>0.05) between seeds.

Effects of Deoxynivalenol and Fumonisins Fed in Combination to Beef Cattle: Immunotoxicity and Gene Expression

We evaluated the effects of a treatment diet contaminated with 1.7 mg deoxynivalenol and 3.5 mg fumonisins (B1, B2 and B3) per kg ration on immune status and peripheral blood gene expression profiles in finishing-stage Angus steers. The mycotoxin treatment diet was fed for a period of 21 days followed by a two-week washout period during which time all animals consumed the control diet. Whole-blood leukocyte differentials were performed weekly throughout the experimental and washout period. Comparative profiles of CD4+ and CD8+ T cells, along with bactericidal capacity of circulating neutrophils and monocytes were evaluated at 0, 7, 14, 21 and 35 days. Peripheral blood gene expression was measured at 0, 7, 21 and 35 days via RNA sequencing. Significant increases in the percentage of CD4-CD8+ T cells were observed in treatment-fed steers after two weeks of treatment and were associated with decreased CD4:CD8 T-cell ratios at this same timepoint (p ≤ 0.10). No significant differences were observed as an effect of treatment in terms of bactericidal capacity at any timepoint. Dietary treatments induced major changes in transcripts associated with endocrine, metabolic and infectious diseases; protein digestion and absorption; and environmental information processing (inhibition of signaling and processing), as evaluated by dynamic impact analysis. DAVID analysis also suggested treatment effects on oxygen transport, extra-cellular signaling, cell membrane structure and immune system function. These results indicate that finishing-stage beef cattle are susceptible to the immunotoxic and transcript-inhibitory effects of deoxynivalenol and fumonisins at levels which may be realistically encountered in feedlot situations.

A randomized trial to evaluate the impact of copra meal hydrolysate on gastrointestinal symptoms and gut microbiome

The impact of copra meal hydrolysate (CMH) on gut health was assessed by conducting a double-blinded, placebo-controlled study. Sixty healthy adult participants, aged 18–40 years were assigned to daily consume 3 g of CMH, 5 g of CMH or placebo in the form of drink powder for 21 days. Consumption of CMH at 3 g/d improved defecating conditions by reducing stool size and also relieved flatulence and bloating symptoms. Fecal samples were collected serially at the baseline before treatment, after the treatment and after a 2-week washout period. The gut microbiomes were similar among the treatment groups, with microbial community changes observed within the groups. Intake of CMH at 3 g/d led to increase microbial diversity and richness. Reduction of the ratio between Firmicutes to Bacteroidetes was observed, although it was not significantly different between the groups. The 3 g/d CMH treatment increased beneficial microbes in the group of fiber-degrading bacteria, especially human colonic Bacteroidetes, while induction of Bifidobacteriaceae was observed after the washout period. Intake of CMH led to increase lactic acid production, while 3 g/d supplement promoted the present of immunoglobulin A (IgA) in stool samples. The 3 g daily dose of CMH led to the potentially beneficial effects on gut health for healthy individuals.

Efficacy and safety of N-acetyl-l-leucine in Niemann–Pick disease type C

Objective To investigate the safety and efficacy of N-acetyl-l-leucine (NALL) on symptoms, functioning, and quality of life in pediatric (≥ 6 years) and adult Niemann–Pick disease type C (NPC) patients. Methods In this multi-national, open-label, rater-blinded Phase II study, patients were assessed during a baseline period, a 6-week treatment period (orally administered NALL 4 g/day in patients ≥ 13 years, weight-tiered doses for patients 6–12 years), and a 6-week post-treatment washout period. The primary Clinical Impression of Change in Severity (CI-CS) endpoint (based on a 7-point Likert scale) was assessed by blinded, centralized raters who compared randomized video pairs of each patient performing a pre-defined primary anchor test (8-Meter Walk Test or 9-Hole Peg Test) during each study periods. Secondary outcomes included cerebellar functional rating scales, clinical global impression, and quality of life assessments. Results 33 subjects aged 7–64 years with a confirmed diagnosis of NPC were enrolled. 32 patients were included in the primary modified intention-to-treat analysis. NALL met the CI-CS primary endpoint (mean difference 0.86, SD = 2.52, 90% CI 0.25, 1.75, p = 0.029), as well as secondary endpoints. No treatment-related serious adverse events occurred. Conclusions NALL demonstrated a statistically significant and clinical meaningfully improvement in symptoms, functioning, and quality of life in 6 weeks, the clinical effect of which was lost after the 6-week washout period. NALL was safe and well-tolerated, informing a favorable benefit-risk profile for the treatment of NPC. Clinicaltrials.gov identifier NCT03759639.

Cardiorespiratory Effects of Three Infusion Doses of Adenosine in Conscious Goats: A Preliminary Study

Adenosine (AD) has been implicated in human healthcare as an endogenous signaling nucleotide in both physiologic and pathologic states. The effects of AD on cardiorespiratory parameters in ruminants has not yet been studied. The objective of this study was to evaluate the cardiac and respiratory changes that resulted from an intravenous AD infusion in goats. Six clinically healthy adult goats weighing 28 ± 2 kg were randomly assigned to one of four treatments in a crossover design with a seven day washout period. The goats received a 0.9 % saline solution (SAL treatment) and three AD treatments (AD 50, 100 and 200) intravenously at a dose rate of 50, 100 and 200 μg/kg/min. Cardiorespiratory and key cardiac parameters were measured before the treatment (baseline), during the infusion (dInf) and at 1, 3, 5 and 10 min after each infusion was discontinued. The AD 100 produced a significant increase in HR (p = 0.001) and the AD 200 resulted in significant rises in HR (p = 0.006) and RR (p = 0.001) compared with the baseline. This study concluded that the AD infusion could trigger an increase in HR and RR in a dose-dependent manner in healthy goats.

505 Efficacy of Pitolisant in the Treatment of Cataplexy in Adults With Narcolepsy

Introduction Pitolisant was initially approved by the FDA in 2019 for the treatment of excessive daytime sleepiness in adult patients with narcolepsy; in 2020, the indication was expanded to include the treatment of cataplexy. Methods Cataplexy data from 7- or 8-week, randomized, placebo-controlled studies (HARMONY-CTP, HARMONY-1) are reviewed and summarized. In HARMONY-CTP, all patients were required to have ≥3 cataplexy attacks per week at baseline; HARMONY-1 enrolled patients with narcolepsy with or without cataplexy. Pitolisant was individually titrated to a maximum potential dose of 35.6 mg/day. The weekly (WRC) or daily (DRC) rate of cataplexy attacks was calculated from patient diaries. Results In HARMONY-CTP (pitolisant, n=54; placebo, n=51), mean baseline WRC was 11.7 in the pitolisant group and 9.6 in the placebo group. In the subset of HARMONY-1 patients with cataplexy (pitolisant, n=17; placebo, n=11), mean baseline DRC was 1.5 and 1.2, respectively. In HARMONY-CTP, least-squares (LS) mean change in WRC was significantly greater for pitolisant versus placebo at Week 2 (-4.1 vs 1.2; P=0.004) and continued through end of treatment (Week 7; -6.5 vs -0.1; P<0.001). In HARMONY-CTP, treatment response was observed in 66.7% of pitolisant-treated versus 25.5% of placebo-treated patients (P<0.001) for WRC reduction ≥50%, and 77.8% versus 33.3% of patients (P<0.001) for WRC reduction ≥25%. In HARMONY-1, LS mean change in DRC was significantly greater for pitolisant versus placebo at Week 5 (-1.04 vs 0.17; P=0.047) and continued through end of treatment (Week 8; -0.96 vs 0.35; P=0.035). In a pooled analysis of patients with high burden of cataplexy (≥15 attacks/week) at baseline (pitolisant, n=20; placebo, n=11), LS mean change in WRC at end-of-treatment assessment was significantly greater for pitolisant (-14.5; baseline, 23.9; final, 9.4) versus placebo (-0.1; baseline, 23.1; final, 23.0; P=0.004). There was no evidence of rebound cataplexy after a 1-week placebo washout period. Conclusion Pitolisant, at once-daily doses of up to 35.6 mg, demonstrated a statistically significant and clinically meaningful reduction in the frequency of cataplexy attacks in adults with narcolepsy, including patients with a high symptom burden. Onset of response was observed within the first few weeks of pitolisant treatment. Support (if any) Bioprojet Pharma and Harmony Biosciences, LLC.