Prebiotic effects of pectooligosaccharides obtained from lemon peel on the microbiota from elderly donors using an in vitro continuous colon model (TIM-2).

The development of new prebiotics capable of modulating the gut microbiota in the elderly has become an area of great interest due to the particular vulnerability and frailty of this population. In the present work, mixtures of pectin-derived oligosaccharides (POS) were manufactured from lemon peel waste and evaluated for their capability to modulate the gut microbiota using, as inoculum, a pool of faeces from elderly donors. Both changes in the microbiota and the metabolic activity were assessed and compared with commercial fructooligosaccharides (FOS) and the standard ileal efflux medium (SIEM) using the TIM-2 in vitro colon model. POS fermentation led to similar or even better effects than FOS at phylum, family and genus levels. Higher increments in beneficial species such as Faecalibacterium prausnitzii and larger alpha diversity values were observed with POS in comparison with FOS and in some cases with SIEM. The PCoA analyses revealed that the microbial profiles resulting from POS and FOS bacterial fermentation were rather similar and differed from those observed after SIEM fermentation. Finally, although butyrate cumulative production was comparable among substrates, the highest short chain fatty acid (SCFA) and the lowest branched chain fatty acid (BCFA) cumulative production was observed in POS experiments. These results support the potential of pectin-derived oligosaccharides as prebiotic candidates targeting gut health in the elderly.

Influence of Previous Failed Antispasticity Therapy on the Efficacy and Tolerability of THC:CBD Oromucosal Spray for Multiple Sclerosis Spasticity.

BACKGROUND: Sativex® (THC:CBD oromucosal spray) is indicated as add-on treatment for patients with moderate to severe multiple sclerosis (MS) spasticity. We aimed to determine whether antispasticity treatment history influenced the efficacy and safety of add-on THC:CBD oromucosal spray in MS spasticity patients. METHODS: Post hoc analysis of an enriched-design clinical trial of THC:CBD oromucosal spray versus placebo, using records of patients under previous and current ineffective antispasticity therapies. Subgroups were patients with at least 1 failed therapy attempt with either baclofen or tizanidine (Group 1) or at least 2 failed therapy attempts with both baclofen and tizanidine (Group 2). SUMMARY: Of 241 patients in the intent-to-treat population, 162 and 57 patients met the criteria for Groups 1 and 2, respectively. In all groups, response on the spasticity 0-10 Numerical Rating Scale was significantly greater with THC:CBD oromucosal spray versus placebo, for minimal clinically important difference (MCID ≥18% improvement vs. baseline) and clinically important difference (CID, ≥30% improvement vs. baseline). THC:CBD oromucosal spray improved spasticity-related symptoms such as sleep quality and timed 10-meter walk independent of the number of prior failed therapy attempts. Tolerability was not influenced by pre-treatment history. CONCLUSIONS: THC:CBD oromucosal spray provided consistent relief with good tolerability in MS spasticity patients irrespective of their antispasticity pre-treatment history.

Effectiveness and Tolerability of THC/CBD Oromucosal Spray for Multiple Sclerosis Spasticity in Italy: First Data from a Large Observational Study.

BACKGROUND: The prospective, non-interventional Mobility Improvement (MOVE) 2 study was designed to provide real life data on clinical outcomes of patients with treatment-resistant multiple sclerosis (MS) spasticity receiving routine treatment with tetrahydrocannabinol (THC):cannabidiol (CBD) oromucosal spray (Sativex®), subsequent to its approval in European countries. METHODS: This interim analysis reports on MOVE 2 patients from Italy. RESULTS: Interim data from 322 patients (58.3% female; mean age 51.1 ± 10.2 years) were analyzed. From baseline to month 3 of treatment (Visit 3), the mean 0-10 Numerical Rating Scale (NRS) score decreased by -19.1% (-1.6 points, p < 0.0001) and the mean modified Ashworth score decreased from 2.6 to 2.3 points (p < 0.0001). At Visit 3, 24.6% of 203 patients with available data were clinically relevant responders (≥30% improvement from baseline NRS score; p < 0.001 vs. baseline). The mean reported dose of THC:CBD oromucosal spray was 6.1 ± 2.5 sprays/day at Visit 1 (1 month) and 5.1 ± 2.6 sprays/day at Visit 3 (range 1-12 sprays/day at both timepoints). Forty-one (13.1%) patients reported at least one adverse event (AE), which included 3 serious AEs (1 unrelated). AEs with an incidence ≥1% were dizziness (5.6%), confusion (2.5%), nausea (1.25%) and somnolence (1.25%). CONCLUSION: In everyday clinical practice in Italy, THC:CBD oromucosal spray provided symptomatic relief of MS spasticity with good tolerability in a relevant number of previously resistant patients.

Sativex(®) and clinical-neurophysiological measures of spasticity in progressive multiple sclerosis.

Despite the proven efficacy of Sativex(®) (9-delta-tetrahydrocannabinol plus cannabidiol) oromucosal spray in reducing spasticity symptoms in multiple sclerosis (MS), little is known about the neurophysiological correlates of such effects. The aim of the study was to investigate the effects of Sativex on neurophysiological measures of spasticity (H/M ratio) and corticospinal excitability in patients with progressive MS. This was a randomized, double-blind, placebo-controlled, crossover study. Consecutive subjects with progressive MS and lower limb spasticity referred to our center were randomized to 4 weeks' treatment (including 2 weeks' titration) with Sativex or placebo, with crossover after a 2-week washout. Clinical and neurophysiological measures (H/M ratio and cortical excitability) of spasticity were assessed. The H/M ratio was the primary outcome, with sample size calculation of 40 patients. Of 44 recruited patients, 34 were analyzed due to 6 drop-outs and 4 exclusions, which lowered the power of the study to show differences between treatments. Neurophysiological measures did not differ significantly according to treatment and did not correlate significantly with clinical response. Response on the modified Ashworth scale (at least 20 % improvement) was significantly more frequent after Sativex than placebo (50 vs 23.5 %; p = 0.041; McNemar). Side effects did not differ significantly according to treatment. Our findings confirm the clinical benefit of Sativex on MS spasticity. The lack of corresponding changes in corticospinal excitability and on the monosynaptic component, of the stretch reflex, although in a limited sample size, points to the involvement of other spinal and supraspinal mechanisms in the physiopathology of spasticity in progressive MS.

Effect of Sativex on spasticity-associated symptoms in patients with multiple sclerosis.

Individuals with multiple sclerosis (MS) spasticity may experience a range of symptoms, such as bladder dysfunction, pain, impaired sleep quality and mobility restrictions that worsen as spasticity severity increases. In this review, the effects of Sativex(®) oromucosal spray on symptoms and functional impairment associated with MS-related spasticity were examined. Across Sativex studies, there was a clear trend for improvement in spasticity-associated symptoms that was more pronounced and sustained over time in Sativex responders. Meaningful symptomatic improvement was achieved within the recommended dosage limit of ≤12 sprays per day. In appropriate patients, Sativex has the potential to minimize the consequences of spasticity-related symptoms on quality of life and reduce the economic burden on healthcare systems.

Cost-effectiveness of Sativex in multiple sclerosis spasticity: new data and application to Italy.

Multiple sclerosis (MS) is a chronic progressive disease that carries a high socioeconomic burden. Spasticity (rigidity and spasms) is common in MS and contributes to MS-related disability. This study aims to evaluate the cost-effectiveness of Sativex(®) (9-delta-tetrahydrocannabinol plus cannabidiol oromucosal spray) when used as add-on therapy for management of resistant MS-related spasticity in the context of the Italian healthcare system. A previously published Markov model-based analysis for the German and Spanish context was replicated, adapting it to the Italian setting. Model parameters were updated to reflect recent findings about MS-related spasticity and use of Sativex in daily clinical practice. The base case incremental cost-effectiveness ratio for Sativex use in Italy over a 5-year period was estimated to be €4968 per quality-adjusted life-year gained (year of costing: 2013). Sativex remained an efficient option in the Italian healthcare context - below the commonly accepted incremental threshold of €30,000 per quality-adjusted life-year gained - when deterministic and probabilistic sensitivity analyses were conducted. Sativex can be regarded as a cost-effective treatment option for patients with MS-related spasticity in Italy.

Impact of Sativex(®) on quality of life and activities of daily living in patients with multiple sclerosis spasticity.

In individuals with multiple sclerosis (MS) spasticity, associated symptoms such as spasms, pain, mobility restrictions and sleep disturbances can interfere with the ability to perform activities of daily living and reduce quality of life (QoL). Recent cross-sectional studies from Europe have confirmed that advancing severity of MS spasticity correlates directly with worsening QoL. The treatment effect of Sativex(®) (GW Pharmaceuticals PLC, Porton Down, UK; Laboratorios Almirall, SA, Barcelona, Spain) on QoL has been evaluated in randomized controlled trials, observational studies conducted under everyday clinical practice conditions and a survey in long-term users. Symptomatic relief of MS spasticity in responders to Sativex was associated with quantifiable improvements in QoL and activities of daily living that were maintained over time. Benefits were perceived by both patients and caregivers.

THC and CBD oromucosal spray (Sativex®) in the management of spasticity associated with multiple sclerosis.

People with multiple sclerosis may present with a wide range of disease symptoms during the evolution of the disease; among these, spasticity can have a marked impact on their well-being and quality of life. Symptom control, including spasticity, remains a key management strategy to improve the patient's well-being and functional status. However, available drug therapies for spasticity sometimes have limited benefit and they are often associated with poor tolerability. Sativex is a 1:1 mix of 9-delta-tetrahydrocannabinol and cannabidiol extracted from cloned Cannabis sativa chemovars, which is available as an oromucosal spray. Clinical experience with Sativex in patients with multiple sclerosis is accumulating steadily. Results from randomized, controlled trials have reported a reduction in the severity of symptoms associated with spasticity, leading to a better ability to perform daily activities and an improved perception of patients and their carers regarding functional status when Sativex was added to the current treatment regimen. Adverse events such as dizziness, diarrhea, fatigue, nausea, headache and somnolence occur quite frequently with Sativex, but they are generally of mild-to-moderate intensity and their incidence can be markedly reduced by gradual 'uptitration'. In summary, initial well-controlled studies with Sativex oromucosal spray administered as an add-on to usual therapy have produced promising results and highlight encouraging avenues for future research.