Pharmacotherapeutic management of lower urinary tract symptoms in Multiple Sclerosis patients.

INTRODUCTION: Multiple Sclerosis (MS) manifests with a plethora of signs and symptoms affecting brain structures and spinal pathways. The multitude of lesions in MS patients makes difficult to establish the relative role of each of them to lower urinary tract symptoms (LUTS). Generally, the subcortical white-matter lesions result in detrusor overactivity, whilst lesions of the spinal cord result in the combined occurrence of detrusor overactivity and detrusor-sphincter dyssynergia (DSD). It has been estimated that 80-90% of patients with MS will suffer from some form of LUTS over the course of the disease. Among LUTS, the most reported is detrusor overactivity which includes urinary urgency, frequent urination, nocturia, and urge urinary incontinence. AREAS COVERED: The authors review the management of lower urinary tract symptoms in MS patients providing their expert opinions on the subject matter. EXPERT OPINION: LUTS affect the quality of life substantially and are associated with a significantly increased mortality. The adequate management is an important challenge for both patients and caregivers with a multidisciplinary approach likely necessary.

Effects of THC/CBD oromucosal spray on spasticity-related symptoms in people with multiple sclerosis: results from a retrospective multicenter study.

INTRODUCTION: The approval of 9-δ-tetrahydocannabinol (THC)+cannabidiol (CBD) oromucosal spray (Sativex®) in Italy as an add-on medication for the management of moderate to severe spasticity in multiple sclerosis (MS) has provided a new opportunity for MS patients with drug-resistant spasticity. We aimed to investigate the improvement of MS spasticity-related symptoms in a large cohort of patients with moderate to severe spasticity in daily clinical practice. MATERIALS AND METHODS: MS patients with drug-resistant spasticity were recruited from 30 Italian MS centers. All patients were eligible for THC:CBD treatment according to the approved label: ≥ 18 years of age, at least moderate spasticity (MS spasticity numerical rating scale [NRS] score ≥ 4) and not responding to the common antispastic drugs. Patients were evaluated at baseline (T0) and after 4 weeks of treatment (T1) with the spasticity NRS scale and were also asked about meaningful improvements in 6 key spasticity-related symptoms. RESULTS: Out of 1615 enrolled patients, 1432 reached the end of the first month trial period (T1). Of these, 1010 patients (70.5%) reached a ≥ 20% NRS score reduction compared with baseline (initial responders; IR). We found that 627 (43.8% of 1432) patients showed an improvement in at least one spasticity-related symptom (SRSr group), 543 (86.6%) of them belonging to the IR group and 84 (13.4%) to the spasticity NRS non-responders group. CONCLUSION: Our study confirmed that the therapeutic benefit of cannabinoids may extend beyond spasticity, improving spasticity-related symptoms even in non-NRS responder patients.

Clinical and Lifestyle Factors and Risk of Amyotrophic Lateral Sclerosis: A Population-Based Case-Control Study.

Background: Amyotrophic lateral sclerosis (ALS) is a progressive, fatal neurodegenerative disease of the motor neurons. The etiology of ALS remains largely unknown, particularly with reference to the potential environmental determinants. Methods: We performed a population-based case-control study in four provinces from both Northern and Southern Italy in order to assess non-genetic ALS risk factors by collecting through tailored questionnaires information about clinical and lifestyle factors. We estimated ALS risk by calculating odds ratio (OR) with its 95% confidence interval (CI) using unconditional logistic regression models adjusted for sex, age and educational attainment. Results: We recruited 230 participants (95 cases and 135 controls). We found a possible positive association of ALS risk with trauma, particularly head trauma (OR = 2.61, 95% CI 1.19-5.72), electric shock (OR = 2.09, 95% CI 0.62-7.06), and some sports, although at a competitive level only. In addition, our results suggest an increased risk for subjects reporting use of private wells for drinking water (OR = 1.38, 95% CI 0.73-2.27) and for use of herbicides during gardening (OR = 1.95, 95% CI 0.88-2.27). Conversely, there was a suggestion of an inverse association with overall fish consumption (OR = 0.27, 95% CI 0.12-0.60), but with no dose-response relation. Consumption of some dietary supplements, namely those containing amino acids and, in the Southern Italy population, vitamins and minerals such as selenium, seemed associated with a statistically imprecise increased risk. Conclusions: Our results suggest a potential etiologic role a number of clinical and lifestyle factors with ALS risk. However, caution is needed due to some study limitations. These include the small sample size and the low number of exposed subjects, which affect statistical precision of risk estimates, the potential for exposure misclassification, and the uncertainties about mechanisms underpinning the possible association between these factors and disease risk.

Sativex in resistant multiple sclerosis spasticity: Discontinuation study in a large population of Italian patients (SA.FE. study).

BACKGROUND: The approval of Sativex for the management of multiple sclerosis (MS) spasticity opened a new opportunity to many patients. In Italy, the healthcare payer can be fully reimbursed by the involved pharma company with the cost of treatment for patients not responding after a 4 week (28 days) trial period (Payment by Results, PbR), and 50% reimbursed with the cost of 6 weeks (42 days) treatment for other patients discontinuing (Cost Sharing, CS). The aim of our study was to describe the Sativex discontinuation profile from a large population of spasticity treated Italian MS patients. METHODS: We collected data of patients from 30 MS centres across the country starting Sativex between January 2014 and February 2015. Data were collected from the mandatory Italian Medicines Agency (AIFA) web-registry. Predictors of treatment discontinuation were assessed using a multivariate Cox proportional regression analysis. RESULTS: During the observation period 631 out of 1597 (39.5%) patients discontinued Sativex. The Kaplan-Meier estimates curve showed that 333 patients (20.8%) discontinued treatment at 4 weeks while 422 patients (26.4%) discontinued at 6 weeks. We found after adjusted modeling that a higher NRS score at T1 (adjHR 2.23, 95% 2.07-2.41, p<0.001) and a lower baseline NRS score (adjHR 0.51 95% CI 0.46-0.56, p<0.001) were predictive of treatment discontinuation. CONCLUSION: These data show that the first 6 weeks are useful in identifying those patients in which Sativex could be effective, thus avoiding the cost of longer term evaluation.

Inhibition of key digestive enzymes related to hyperlipidemia and protection of liver-kidney functions by Cystoseira crinita sulphated polysaccharide in high-fat diet-fed rats.

The objective of this current study was to investigate the possible hyperlipidemic and antioxidative effects of Cystoseira crinita sulfated polysaccharide (CCSP) in rats fed with a high-fat diet, exhibited an inhibitory activity on pancreatic lipase in vitro. In vivo administration of this extract to HFD-rats lowered body weight and potentially inhibited key enzymes of lipid metabolism and absorption as lipase activity in both plasma and small intestine, which led to a notable decrease of blood LDL- cholesterol (LDL-Ch) and triglycerides (TG) levels, and an increase in HDL-cholesterol (HDL-Ch) levels in HFD-rats. CCSP was also observed to protect the liver-kidney functions efficiently, by decreasing of aspartate transaminase (AST), alanine transaminase (ALT), lactate dehydrogenase (LDH) and Creatine phosphokinase (CPK) activities and creatinine, albumin, T-bilirubin, uric acid, and urea rates in plasma. The histological analysis of liver and kidney tissues further established the positive effect of CCSP.

Health Authorities Data Collection of THC:CBD Oromucosal Spray (L'Agenzia Italiana del Farmaco Web Registry): Figures after 1.5 Years.

BACKGROUND: In Italy, all prescriptions for THC:CBD oromucosal spray for treatment of multiple sclerosis (MS) spasticity are linked to the official Agenzia Italiana del Farmaco (AIFA) web-based registry, which tracks the effectiveness and tolerability of medications in a prospective and observational manner. METHODS: AIFA e-registry data for THC:CBD oromucosal spray collected between January 2014 and February 2015 for 1,534 patients from 30 large Italian specialized MS centres were compiled. Patients had a long disease history (17.6 ± 8.6 years) and significant impairment (mean Expanded Disability Status Scale score 6.4 ± 1.2). MS spasticity was evaluated using the 0-10 numerical rating scale (NRS). RESULTS: After the first month titration and trial period, 61.9% of patients achieved sufficient improvement in spasticity (≥20% NRS) to qualify for continued treatment. After 6 months, clinically meaningful ≥30% NRS improvement was recorded in 40.2% of patients continuing with treatment. Spasticity-associated symptoms such as cramps and nocturnal spasms improved in most responding patients. Mean reported doses of THC:CBD oromucosal spray (6.2-6.7 sprays/day) were lower than those reported in clinical trials. Adverse events (mainly mild to moderate) were reported by 15% of patients; no new safety concerns beyond the approved label were identified. CONCLUSION: The results of the AIFA e-registry analysis align with those of other THC:CBD observational projects and reaffirm the characteristics of this therapeutic option in the management of treatment-resistant MS spasticity, a frequently overlooked symptom.

Anti-obesity and lipid lowering effects of Cymodocea nodosa sulphated polysaccharide on high cholesterol-fed-rats.

This study aims to evaluate for the first time the effects of Cymodocea nodosa sulphated polysaccharide (CNSP) on lipase activity in vitro and in vivo to high fat diet (HFD)-rats on body weight, lipid profile and liver-kidney functions. The administration of CNSP decreases the body weight and inhibits lipase activity of obese rats in serum and intestine as compared with untreated HDF-rats. This decrease in lipase activity leads to lipid regulation shown by the decrease of total cholesterol (T-Ch), triglycerides (TG) and low density lipoprotein cholesterol (LDL-C) and an increase in high density lipoprotein cholesterol (HDL-C) levels in HFD-rats. Additionally, CNSP administration to HFD-rats induces anti-oxidant activity observed by the increase of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPX) activities and the decrease in Thiobarbituric acid reactive substances (TBARS) levels and protects liver-kidney functions proven by a decrease in the levels of toxicity parameters in blood.

Clinical case reviews and poster sessions in multiple sclerosis spasticity: main outcomes and highlights.

BACKGROUND: Individuals with multiple sclerosis (MS) spasticity present with a range of symptoms and disability levels that are frequently challenging to manage. Summary : Clinical case reviews in treatment-resistant MS spasticity were presented in five country-specific sessions conducted in parallel at the MS Experts Summit. Attendees at the Norwegian session discussed early response to new treatments for severe spasticity and highlighted the importance of titrating THC:CBD oromucosal spray (Sativex®) when adding it to baclofen. The French group focussed on MS symptoms and patient characteristics that interact with spasticity and agreed on a list of minimum ratings for diagnosis of MS spasticity symptoms. Attendees at the Spanish session concurred that THC:CBD oromucosal spray is effective and well tolerated as add-on therapy in treatment-resistant MS spasticity, particularly for pain, spasms and gait disturbances. The Italian group discussed the use of add-on THC:CBD oromucosal spray and other possible combination therapies for treatment-resistant MS spasticity. Attendees at the German session highlighted the need to address trigger factors for MS spasticity to reduce the potential for impact on activities of daily living (ADL) and quality of life (QoL). Three innovative studies of MS spasticity from the poster session were selected for closer review. The MOVE 1 EU epidemiological study indicated that, across western Europe, patients with MS spasticity continue to have unmet management needs. A literature review demonstrated that symptomatic relief of MS spasticity in patients who respond to THC:CBD oromucosal spray translates into sustainable improvements in ADL and QoL. Enriched-design studies of medications targeting the endocannabinoid system require careful interpretation due to possible pharmacodynamic 'priming', i.e. carry-over effects of successful active treatment during the enrichment phase. Key Messages: Sharing experiences of clinical practice, including experience with the use of THC:CBD oromucosal spray, may be useful to overcome some of the challenges in the overall management of patients with moderate to severe treatment-resistant MS spasticity.

The pharmacokinetics of glatiramer acetate for multiple sclerosis treatment.

INTRODUCTION: Multiple sclerosis (MS) is a T-cell-mediated disease affecting the central nervous system (CNS), characterized by demyelination and axonal degeneration. INF-ß1b was the first drug approved for MS patients in 1993. In 1996, glatiramer acetate (GA), a synthetic copolymer, was approved in the USA for the treatment of relapsing-remitting MS (RRMS) and clinically isolated syndrome (CIS). Although the immunological action of GA has been fully investigated, the exact mechanisms of action of GA are still not completely elucidated. Several in vitro studies on mice and human antigen-presenting cells (APCs) have shown that GA is able to bind to the major histocompatibility complex (MHC), on the surface of APCs, recognizing myelin basic protein (MBP). AREAS COVERED: This review explores the pharmacological characteristics of GA, its mechanism of action and its pharmacokinetics properties. The article also provides information on the efficacy, tolerability and an overview of the most important clinical data on GA. EXPERT OPINION: Despite the development of novel compounds, it is not surprising that GA is, to date, one of the most prescribed drugs for RRMS patients and CIS patients. The proven efficacy and the mild adverse events, makes GA a good therapeutic option in the early stage of the disease. This is particularly useful for patients who suffer flu-like symptoms from other RRMS therapies as an alternative.