Current Disease-modifying Drugs Research Articles

Ocimum basilicum attenuates ethidium bromide-induced cognitive deficits and pre-frontal cortical neuroinflammation, astrogliosis and mitochondrial dysfunction in rats.

Multiple sclerosis (MS) is a chronic neurodegenerative disorder with clinical symptoms of neuroinflammation and demyelination in the central nervous system. Recently, herbal medicines are clinically effective against MS as the current disease-modifying drugs have limited effectiveness. Hence, the present study evaluated the therapeutic potential of Ocimum basilicum essential oil (OB) in ethidium bromide (EB)-induced cognitive deficits in the male rats. Further, the effect of OB (50, 100 and 200μL/kg) was evaluated on EB-induced neuroinflammation, astrogliosis and mitochondrial dysfunction in the pre-frontal cortex (PFC) of the animals. The EB was injected through bilateral intracerebroventricular route into hippocampus to induce MS-like manifestations in the rats. OB (100 and 200μL/kg) and Ursolic acid (UA) significantly reduced the EB-induced cognitive deficits in Morris water maze and Y-maze test paradigms. OB (100 and 200μL/kg) and UA significantly attenuated the EB-induced neuroinflammation in terms of increase in the levels of pro-inflammatory cytokines (TNF-alpha and IL-6) in the rat PFC. Further, OB (100 and 200μL/kg) and UA significantly attenuated the EB-induced astrogliosis in terms of increase in the levels of GFAP (Glial fibrillary acidic protein) and Iba-1 (Ionized calcium binding adaptor molecule-1) in the rat PFC. In addition, OB (100 and 200μL/kg) and UA significantly attenuated the EB-induced decrease in the mitochondrial function, integrity, respiratory control rate and ADP/O in the PFC of the rodents. Moreover, OB (100 and 200μL/kg) and UA significantly reduced the EB-induced mitochondria-dependent apoptosis in the PFC of the rat. Hence, it can be presumed that OB could be a potential alternative drug candidate in the pharmacotherapy of MS.

Modeling the impact of patient treatment preference on health outcomes in relapsing-remitting multiple sclerosis

Aims: Model how moving from current disease-modifying drug (DMD) prescribing patterns for relapsing-remitting multiple sclerosis (RRMS) observed in the United Kingdom (UK) to prescribing patterns based on patient preferences would impact health outcomes over time.Materials and methods: A cohort-based Markov model was used to measure the effect of DMDs on long-term health outcomes for individuals with RRMS. Data from a discrete choice experiment were used to estimate the market shares of DMDs based on patient preferences (i.e. preference shares). These preference shares and real-world UK market shares were used to calculate the effect of prescribing behavior on relapses, disability progression, and quality-adjusted life-years (QALYs). The incremental benefit of patient-centered prescribing over current practices for the UK RRMS population was then estimated; scenario and sensitivity analyses were also conducted.Results: Compared to current prescribing practices, when UK patients with RRMS were treated following patient preferences, health outcomes were improved. This population was expected to experience 501,690 relapses and gain 1,003,263 discounted QALYs over 50 years under patient-centered prescribing practices compared to 538,417 relapses and 958,792 discounted QALYs under current practices (−6.8% and +4.6%, respectively). Additionally, less disability progression was observed when prescribed treatment was based on patient preferences. In a scenario analysis where only oral treatments were considered, the results were similar, although the magnitude of benefit was smaller. Number of relapses was most sensitive to how the annualized relapse rate was modeled; disability progression was most sensitive to mortality rate assumptions.Limitations: Treatment efficacy estimates applied to various models in this study were based on data derived from clinical trials, rather than real-world data; the impact of patient-centered prescribing on treatment adherence and/or switching was not modeled.Conclusions: The population of UK RRMS patients may experience overall health gains if patient preferences are better incorporated into prescribing practices.

Chapter 5 - Behavioral symptomatology and psychopharmacology of Lewy body dementia

Lewy body dementia (LBD) is an umbrella term for major neurocognitive disorders caused by Lewy body pathology. Parkinson's disease dementia (PDD) and Dementia with Lewy bodies (DLB) are the two main syndromes in LBD. LBDs typically present with cognitive impairment, cholinergic deficiency, neuropsychiatric symptoms such as visual hallucinations and paranoid delusions, as well as parkinsonian symptoms. Due to the urgency in diagnosing LBD early in the disease course to provide the most optimal management of these syndromes, it is important that clinicians elicit the most clinically significant symptoms during patient encounters. The focus of this chapter is to discuss current LBD classification systems and assessments, neuropathology of LBDs, behavioral symptomatology, contemporary management options, and possible future targets of treatment. PubMed was searched to obtain reviews and studies that pertain to classification, behavioral symptomatology, neurobiology, neuroimaging, and treatment of LBDs. Articles were chosen with a predilection to more recent clinical trials and systematic reviews or meta-analyses. Updates to diagnostic criteria have increased clinical diagnostic sensitivity and specificity. Current therapeutic modalities are limited as there is no current disease-modifying drug available. Cholinesterase inhibitors have been reported to be effective in decreasing neuropsychiatric and cognitive symptoms. Neuroleptics should be avoided unless clinically indicated. There is a paucity of studies investigating treatment options for mood symptoms. Current novel targets of treatment focus on decreasing α-synuclein burden. LBDs are a group of dementia syndromes that affect a significant portion of the elderly population. Early diagnosis and treatment is necessary to improve patient quality of life with current treatment options more focused on alleviating severe symptomatology rather than modifying disease pathology.

Health Outcomes and Lifestyle in a Sample of People With Multiple Sclerosis (HOLISM): Longitudinal and Validation Cohorts.

Objective: To report the methodology and summary data of the Health Outcomes and Lifestyle In a Sample of people with Multiple sclerosis (HOLISM) longitudinal and validation cohorts. We report (1) data on participation, socio-demographics, disease characteristics, medication use, modifiable lifestyle risk factor exposures, and health outcomes of the HOLISM longitudinal cohort 2.5-years post enrolment; (2) attrition at this 2.5-year wave; and (3) baseline characteristics of the associated HOLISM validation cohort.Methods: The HOLISM longitudinal study recruited people internationally with self-reported diagnosed multiple sclerosis (MS) through web 2.0 platforms and MS society newsletters. Participants, first recruited in 2012, were invited 2.5-years later to participate in a follow-up survey. At both time points, participants completed a comprehensive online questionnaire of socio-demographics, modifiable lifestyle exposures, and health outcomes using validated and researcher-designed tools. The same methodology was used to recruit a new sample: the HOLISM validation cohort. Characteristics were explored using summary measures.Results: Of 2,466 people with MS at baseline, 1,401 (56.8%) provided data at 2.5-year follow-up. Attrition was high, likely due to limited amount of contact information collected at baseline. Completion of the 2.5-year wave was associated with healthier lifestyle, and better health outcomes. Participants completing follow-up had diverse geographical location, were predominantly female, married, unemployed or retired. At 2.5-year follow-up, nearly 40% were overweight or obese, most were physically active, non-smokers, consumed little alcohol, used vitamin D/omega-3 supplements, and 42% reported current disease-modifying drug use. Thirty percentage of reported cane or gait disability, while 13% relied on major mobility supports (Patient Determined Disease Steps). Approximately half the respondents reported a comorbidity, 63% screened positive for clinically significant fatigue (Fatigue Severity Scale), and 22% screened positive for depression (Patient Health Questionnaire-9). The validation cohort's characteristics were mostly consistent with previously reported HOLISM baseline data.Conclusions: Exploring prospective associations of modifiable environmental/behavioral risk factors with health outcomes in this international longitudinal sample of people with MS will be beneficial to MS research. Impacts of attrition and selection bias will require consideration. The validation cohort provides opportunity for replication of previous findings, and also for temporal validation of predictive models derived from the HOLISM cohort.

Regulation of Arthritis Severity by the Acid Sphingomyelinase

Background/Aims: Rheumatoid arthritis is a chronic autoimmune disease hallmarked by inflammation in synovial joints. Treatment is hampered by the lack of a cure and current disease-modifying drugs are associated with potentially severe toxicities. Methods: We investigated arthritis severity by measuring joint swelling and pro-inflammatory cytokine production in a murine experimental model of inflammatory arthritis (antigen-induced arthritis). We analyzed acid sphingomyelinase knock-out mice and wild-type littermates, as well as mice treated with the pharmacological acid sphingomyelinase inhibitor amitriptyline. Results: Genetic ablation or pharmacological inhibition of acid sphingomyelinase reduced joint swelling and levels of pro-inflammatory cytokines in the arthritic joint. Conclusion: We identified acid sphingomyelinase as a novel druggable target in rheumatoid arthritis. Functional inhibitors of acid sphingomyelinase have been clinically used for decades, are well tolerated and suitable for long-term treatment. They would be immediately available for clinical development as a novel rheumatoid arthritis therapy.

Relationship of EQ-5D quality of life with the presence of co-morbidity and extra-articular features in patients with rheumatoid arthritis

Rheumatoid arthritis (RA) is associated with extra-articular features (ExRA) and other co-morbidities. The aim of this study is to quantify their relative contribution to quality of life (QOL) in patients with RA. A consecutive series of 114 ambulatory RA patients aged between 40 and 65 years were assessed by a research nurse on a single occasion. Assessment included a patient questionnaire (including EQ-5D), medication review and fasting venous blood sample. Medical records were reviewed by a rheumatologist for co-existing conditions. Multiple linear regression was used to adjust mean differences in EQ-5D in the presence/absence of co-existing conditions for age, sex, university education, arthritis duration, rheumatoid factor, erythrocyte sedimentation rate, current disease-modifying drug therapy, previous hand joint erosions and joint surgery. Mean age was 54 years (82% female) and median arthritis duration 10 years. Unadjusted EQ-5D was -0.09 (95% CI -0.18 to -0.01) lower in patients with any co-existing condition. EQ-5D scores were inversely correlated with the overall number of co-existing conditions (Spearman's ρ -0.31, p = 0.001), number of co-morbidities (ρ -0.22, p = 0.02) and number of ExRA features (ρ -0.22, p = 0.02). There was a linear trend of lower EQ-5D with increasing number of co-existing conditions (p = 0.003). EQ-5D was -0.18 (95% CI -0.33 to -0.02) lower in the presence of more than two co-existing conditions compared to none. Co-morbidity and ExRA features were associated with comparable adjusted reductions (-0.05 vs. -0.06) in EQ-5D scores. A wide range of co-existing conditions are associated with poorer QOL in patients with RA.

Evidence-based assessment of potential use of fingolimod in treatment of relapsing multiple sclerosis

Multiple sclerosis is an autoimmune inflammatory demyelinating disease of the central nervous system and represents one of the most common causes of chronic neurologic disability in young adults. All the current disease-modifying drugs are administered parenterally, and can be associated with varying degrees of injection site or infusion-related reactions. Together with other side effects, the parenteral route of administration is one of the key factors affecting adherence to therapy in multiple sclerosis. Fingolimod (FTY720) is an immunomodulator that acts on sphingosine 1-phosphate (S1P) receptors and is the first oral drug approved by the US Food and Drug Administration for the treatment of relapsing-remitting multiple sclerosis. Downmodulation of S1P receptor type 1 (S1P1) slows the egress of lymphocytes from lymph nodes and recirculation to the central nervous system, reduces astrogliosis, and inhibits angiogenesis during chronic neuroinflammation. Fingolimod also regulates the migration of B cells and dendritic cells, and enhances endothelial barrier function. Results from Phase II and III clinical trials provide robust evidence of the efficacy of fingolimod in relapsing-remitting multiple sclerosis. While some caution should be exercised in terms of safety issues, the introduction of fingolimod represents a great advance in the treatment of relapsing-remitting multiple sclerosis. The pharmacologic data on fingolimod and its efficacy and safety in multiple sclerosis are reviewed in this paper.

Emerging oral treatments in multiple sclerosis – clinical utility of cladribine tablets

Multiple sclerosis (MS) is a chronic inflammatory disorder of the central nervous system (CNS) that represents one of the first causes of neurological disability in young adults. Although the pathogenesis of MS is still unclear, an autoimmune mechanism has been demonstrated. According to this evidence in the last 15 years different treatments acting on the immune system have been developed. Current disease-modifying drugs (DMDs) for MS require regular and frequent parenteral administration and are associated with limited long-term treatment adherence. Moreover the clinical efficacy of these disease-modifying drugs is suboptimal. Thus, there is an important need for the development of new therapeutic strategies. Several oral therapies (fingolimod, fumaric acid, teriflunomide, laquinimod) are in development; Among these cladribine is the only therapy with the potential for short-course dosing. Cladribine is an immunosuppressant that offers sustained regulation of the immune system through a preferential lymphocyte depleting action. Cladribine has a well-characterized and well-known safety profile, derived from more than 15 years of use of the parenteral formulation both in the oncology field and in MS. This paper reviews the new oral emerging treatments and presents the available data about the use of cladribine in MS and the future perspective of its clinical use.

Development of oral cladribine for the treatment of multiple sclerosis

Multiple sclerosis (MS) is a chronic immune-mediated disorder of the CNS in which autoreactive CD4+ and CD8+ T lymphocytes, B lymphocytes, antibodies, macrophages and cytokines synergize to attack myelin sheaths and injure underlying axons. Current disease-modifying drugs (DMDs) for MS require regular and frequent parenteral administration and are associated with limited long-term treatment adherence. Of all the potential new oral MS agents in development, cladribine is the only therapy with the potential for short-course dosing. Cladribine is an immunosuppressant that offers targeted, sustained regulation of the immune system and that has a well-characterized safety profile, derived from more than 15 years of use of the parenteral formulation in oncology indications and MS. This paper discusses the need for new MS therapies to improve treatment adherence, and reviews the mechanism of action, existing efficacy and safety data, and the clinical development of oral cladribine. The need for continuous risk monitoring for all new potent immunoactive drugs under development is emphasized. Preliminary results of the 96-week, double-blind, randomized, placebo-controlled, multicenter CLARITY (CLAdRIbine Tablets Treating MS OrallY) study are encouraging and provide the first complete phase III data on an oral DMD for MS.

Existing therapies for multiple sclerosis offer proven efficacy and safety

There are currently six disease-modifying drugs approved for relapsing forms of multiple sclerosis. Their efficacy has been proven in multiple clinical trials. The four therapies licensed as first-line agents (three formulations of interferon-beta and one of glatiramer acetate) have well-established short-term and long-term safety profiles, with manageable adverse events. Results of recent trials suggest that current disease-modifying drugs may have better on-treatment disease suppression than was predicted by the results of the original pivotal studies. Although these therapies are all parenterally administered, a number of technological advances have improved various aspects of injection tolerability and enhanced acceptability, so that the impact of self-injection on the patient's life is minimized. Several promising oral disease-modifying drugs are now in phase III development. However, as these drugs are new to multiple sclerosis therapy, their short-term and long-term safety profiles are unknown. Although novel therapies for multiple sclerosis, particularly orally administered drugs, are eagerly awaited, they will not immediately replace the tried and trusted options.

Effective Multiple Sclerosis Management Through Improved Patient Assessment

Multiple sclerosis (MS) is a complex disease with a wide range of clinical manifestations. Current disease-modifying drugs (DMDs) are effective, but they are associated with effects that may negatively influence treatment compliance. A recent nursing advisory board of MS nurse experts from the Midwest discussed management approaches that can enhance DMD compliance and improve patient satisfaction and quality of life. One such approach is the use of patient questionnaires as tools to assess signs and symptoms of MS and treatment-related adverse effects. Information gained in this manner is beneficial to MS healthcare professionals as well as patients and has the potential to improve treatment compliance and outcomes and disease management.

Emerging oral therapies for multiple sclerosis

Current disease-modifying drugs (DMDs) have positively affected the treatment of relapsing-remitting multiple sclerosis (RRMS); however, the requirement for long-term injections imposes a burden on patients and may lead to reduced adherence in some cases. Furthermore, not all patients respond adequately to current DMDs, suggesting that certain patients require different therapeutic approaches. Therefore, alternative MS treatments with less invasive routes of administration and new modes of action are needed to expand the current treatment repertoire, increase patient satisfaction and adherence, and thereby improve efficacy. This review discusses the current unmet need for an orally administered treatment for RRMS, including potential benefits of this route of administration, and implications for improved treatment outcomes. Oral drugs that are currently in Phase II/III clinical development are discussed.

Long-term experience with current disease-modifying drugs in multiple sclerosis

■ Abstract Five different immunomodulatory treatments have been developed and approved for the treatment of multiple sclerosis. These have been shown to be efficacious over the short-term in the reduction of relapse rates, measures of disease activity and disease progression in randomised, placebo-controlled trials. However, multiple sclerosis is a chronic progressive disease of variable course in which long-term benefits of treatment are critically important. It is not possible to obtain data on long-term outcome from placebo-controlled trials and observational open-label designs are required. Ideally, these would involve prospective follow-up of all included patients over decades. Long-term studies with (3-interferons have generally used retrospective designs which have important limitations in terms of case ascertainment and selection bias. Nonetheless, they suggest that treatment benefit may be maintained over time. Glatiramer acetate is the only immunomodulatory treatment which has been studied prospectively over a period of ten years, and for which outcomes have been compared between subjects with continuous treatment and those in whom glatiramer acetate was discontinued. Ten-year data showed suppression of relapse rate to be maintained with 62 % showing stable or improved disability levels. Disability progression was less than what would be expected from natural history studies of untreated patients with multiple sclerosis.