Potential Effects of Cannabidiol as a Wake-Promoting Agent

Over the last decades, the scientific interest in chemistry and pharmacology of cannabinoids has increased. Most attention has focused on ∆⁹-tetrahydrocannabinol (∆⁹-THC) as it is the psychoactive constituent of Cannabis sativa (C. sativa). However, in previous years, the focus of interest in the second plant constituent with non-psychotropic properties, cannabidiol (CBD) has been enhanced. Recently, several groups have investigated the pharmacological properties of CBD with significant findings; furthermore, this compound has raised promising pharmacological properties as a wake-inducing drug. In the current review, we will provide experimental evidence regarding the potential role of CBD as a wake-inducing drug.     

The Effectiveness of Dimethyl Fumarate Monotherapy in the Treatment of Relapsing-Remitting Multiple Sclerosis: A Systematic Review and Meta-Analysis

Background:

Dimethyl fumarate (BG-12, Tecfidera®) is a new oral drug approved by FDA and EMA in March 2013 for relapsing – remitting multiple sclerosis (RRMS). The drug was much anticipated because of its possible superiority over currently available medications: fingolimod and teriflunomide as the only MS treatments currently available in oral form.

Objective:

The aim of this systematic review with meta-analysis was to assess the efficacy and safety of BG-12 in the treatment of RRMS.

Methods:

A systematic literature search was conducted in Medline/PubMed, EMBASE, and Cochrane Library up till 3^rd November, 2013. We sought all published randomized clinical trials evaluating the use of dimethyl fumarate for the treatment of patients with RRMS. All included studies were critically appraised and analyzed with the use of Review Manager 5.1.0. software according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement protocol.

Results:

Two trials, DEFINE and CONFIRM involved 2 651 patients and compared dimethyl fumarate taken either two or three times daily with placebo in patients with RRMS. Additionally in CONFIRM trial third group of patients received glatiramer acetate. The overall results of the meta-analysis showed that BG-12 (at both dosages) given to patients with RRMS is safe and statistically significantly more effective than placebo in reducing the proportion of patients who had a relapse by 2 years, the rate of disability progression and the mean number of gadolinium-enhancing lesions at 2 years. The comparison between BG-12 and glatiramer acetate revealed that the analyzed agent could potentially be more effective in the treatment of RRMS.

Conclusions:

Despite limited RCTs data available, both analyzed BG-12 regimens showed their efficacy on clinical disease parameters and other measures of disease activity in RRMS. The safety profile of the study agent was acceptable.     

Role of Gut Microbiota in Multiple Sclerosis and Potential Therapeutic Implications

The role of gut microbiota in health and diseases has been receiving increased attention recently. Emerging evidence from previous studies on gut-microbiota-brain axis highlighted the importance of gut microbiota in neurological disorders. Multiple sclerosis (MS) is a chronic, inflammatory, demyelinating disease of the central nervous system (CNS) resulting from T-cell-driven, myelin-directed autoimmunity. The dysbiosis of gut microbiota in MS patients has been reported in published research studies, indicating that gut microbiota plays an important role in the pathogenesis of MS. Gut microbiota have also been reported to influence the initiation of disease and severity of experimental autoimmune encephalomyelitis, which is the animal model of MS. However, the underlying mechanisms of gut microbiota involvement in the pathogenesis of MS remain unclear. Therefore, in this review, we summerized the potential mechanisms for gut microbiota involvement in the pathogenesis of MS, including increasing the permeability of the intestinal barrier, initiating an autoimmune response, disrupting the blood-brain barrier integrity, and contributing to chronic inflammation. The possibility for gut microbiota as a target for MS therapy has also been discussed. This review provides new insight into understanding the role of gut microbiota in neurological and inflammatory diseases.     

Simvastatin: Multiple Sclerosis

This Hospital Pharmacy feature is extracted from Off-Label Drug Facts, a publication available from Wolters Kluwer Health. Off-Label Drug Facts is a practitioner-oriented resource for information about specific drug uses that are unapproved by the US Food and Drug Administration. This new guide to the literature enables the health care professional or clinician to quickly identify published studies on off-label uses and determine if a specific use is rational in a patient care scenario. References direct the reader to the full literature for more comprehensive information before patient care decisions are made. Direct questions or comments regarding Off-Label Drug Uses to ude.uk@larenegj.     

Atorvastatin: Multiple Sclerosis

This Hospital Pharmacy feature is extracted from Off-Label Drug Facts, a publication available from Wolters Kluwer Health. Off-Label Drug Facts is a practitioner-oriented resource for information about specific drug uses that are unapproved by the US Food and Drug Administration. This new guide to the literature enables the health care professional or clinician to quickly identify published studies on off-label uses and determine if a specific use is rational in a patient care scenario. References direct the reader to the full literature for more comprehensive information before patient care decisions are made. Direct questions or comments regarding Off-Label Drug Uses to ude.uk@larenegj     

Epstein–Barr Virus Infection and Multiple Sclerosis: A Review

Epstein–Barr virus (EBV) infection results in a life-long persistence of the virus in the host’s B-lymphocytes and has been associated with numerous cancers including Burkitt’s lymphoma, Hodgkin lymphoma, and nasopharyngeal carcinoma. There is considerable evidence that EBV infection is a strong risk factor for the development of multiple sclerosis. Early age at primary EBV infection is typically asymptomatic, but primary infection during adolescence or adulthood often manifests as infectious mononucleosis, which has been associated with a two- to threefold increased risk of MS. Most importantly, MS risk is extremely low in individuals who are EBV negative, but it increases several folds following EBV infection. Additional evidence supporting a role for EBV in MS pathogenesis includes the observations of elevated antibodies to EBV antigens (especially EBV nuclear antigen-1) prior to the onset of MS, and an increased risk of MS among EBV-positive children. The biological mechanism by which EBV may cause MS is not known, but several possibilities are discussed.     

免疫调节药物治疗多发性骨髓瘤发生深静脉血栓风险的系统评价和Meta分析

目的:系统评价免疫调节药物(IMiDs)治疗多发性骨髓瘤(MM)发生深静脉血栓(DVT)的风险,为临床安全用药提供参考。方法:计算机检索自建库起至2018年12月31日PubMed、Web of Science、Cochrane图书馆、中国期刊全文数据库、万方数据、中文科技期刊数据库、www.ClinicalTrials.gov中有关IMiDs治疗MM患者发生DVT风险的随机对照试验(RCT)。使用Stata 12.0统计软件对DVT发生率和相对危险度(RR)进行Meta分析,使用GRADE系统对所得证据进行评估分级。结果:共纳入11项RCT,合计3 365例患者(其涉及3种药)。Meta分析结果显示,使用IMiDs治疗MM时DVT的发生率为7.3%[95%CI(4.5%,10.2%)]。与常规化疗相比,IMiDs治疗MM发生DVT的风险更高[RR=3.57,95%CI(2.42,5.27),P<0.01]。不同治疗阶段的亚组分析显示,IMiDs治疗诱导阶段MM患者后,DVT发生的风险较常规化疗方案增加386%[RR=4.86,95%CI(2.85,8.30),P<0.01],该证据级别为中等;与常规化疗方案相比,IMiDs在维持阶段[RR=2.40,95%CI(0.70,8.27),P=0.16]和复发阶段[RR=2.01,95%CI(0.74,5.46),P=0.17]治疗MM患者DVT发生风险无显著性差异。沙利度胺、来那度胺致DVT发生率分别为11%[95%CI(9%,13%)]、3%[95%CI(2%,4%)]。结论:现有证据表明,IMiDs在MM治疗发生DVT的风险较高,临床用药需关注。     

Ketamine as a Potential Treatment for Suicidal Ideation: A Systematic Review of the Literature

Objective

To review the published literature on the efficacy of ketamine for the treatment of suicidal ideation (SI).

Methods

The PubMed and Cochrane databases were searched up to January 2015 for clinical trials and case reports describing therapeutic ketamine administration to patients presenting with SI/suicidality. Searches were also conducted for relevant background material regarding the pharmacological function of ketamine.

Results

Nine publications (six studies and three case reports) met the search criteria for assessing SI after administration of subanesthetic ketamine. There were no studies examining the effect on suicide attempts or death by suicide. Each study demonstrated a rapid and clinically significant reduction in SI, with results similar to previously described data on ketamine and treatment-resistant depression. A total of 137 patients with SI have been reported in the literature as receiving therapeutic ketamine. Seven studies delivered a dose of 0.5 mg/kg intravenously over 40 min, while one study administered a 0.2 mg/kg intravenous bolus and another study administered a liquid suspension. The earliest significant results were seen after 40 min, and the longest results were observed up to 10 days postinfusion.

Conclusion

Consistent with clinical research on ketamine as a rapid and effective treatment for depression, ketamine has shown early preliminary evidence of a reduction in depressive symptoms, as well as reducing SI, with minimal short-term side effects. Additional studies are needed to further investigate its mechanism of action, long-term outcomes, and long-term adverse effects (including abuse) and benefits. In addition, ketamine could potentially be used as a prototype for further development of rapid-acting antisuicidal medication with a practical route of administration and the most favorable risk/benefit ratio.     

Multiple Sclerosis: Pathogenesis and Treatment

Multiple sclerosis (MS) is a chronic inflammatory autoimmune demyelinating disease of the central nervous system. It affects approximately 400,000 people in the United States and onset is usually during young adulthood. There are four clinical forms of MS, of which relapsing remitting type is the most common. As the etiology of MS is unknown, finding a cure will remain challenging. The main mechanism of injury appears to be inflammation and 8 agents are now FDA approved to help control MS. These agents for relapsing forms of MS target different parts of the immune system, with the end goal of decreasing and avoiding further inflammation. No agents are FDA approved for the primary progressive version of MS. FDA approved agents include four preparations of interferon β (Avonex, Rebif, Betaseron and Extavia), glatiramer acetate (Copaxone), mitoxantrone (Novantrone), natalizumab (Tysabri) and fingolimod (Gilenya). There are several drug undergoing phase II and III trials. The heterogeneity of the MS disease process, individual patient response, and medication toxicities continue to challenge the treating physician.     

Pharmacogenetic Development of Personalized Medicine: Multiple Sclerosis Treatment as a Model

The goal of pharmacogenetics is to identify "genetic fingerprints" that may predict a patient's response to pharmaceutical treatment. The use of pharmacogenetics replaces the trial-and-error strategy, which governs much of our clinical decision-making regarding treatment allocation in current medical practice, with individually tailored therapy. We review a pharmacogenetic research model, which implements high-throughput single nucleotide polymorphism technology to establish the correlation between drug-responsiveness and genetic polymorphisms of Copaxone(R)-treated multiple sclerosis patients. Implementation of similar pharmacogenetic approaches may promote the development of personalized medicine in multiple sclerosis as well as in other diseases. (c) 2002 Prous Science. All rights reserved.     

多发性硬化的临床研究进展

多发性硬化在临床上较为常见,属于发病率较高的中枢神经系统以及免疫系统疾病,可导致患者出现视神经病变以及平衡性失调,另外,智力减退、失语也是该疾病患者的临床表现,部分病情较为严重的患者可发生瘫痪,对患者的生命健康造成严重不良影响。目前,临床上为了有效防治多发性硬化,非常重视该疾病患者的诊断和治疗,提出了药物治疗方法来显著改善患者的临床症状以及改善患者预后。笔者针对多发性硬化疾病的诊断和治疗进行如下综述。     

多发性硬化的治疗进展

多发性硬化(nultiple sclerosis,ms)是一种免疫相关的中枢神经系统炎性脱髓鞘疾病.它可以累及脑组织和脊髓的任何部位,导致瘫痪、感觉障碍、失明、癫痫发作、认知障碍等各种临床症状,且会反复发作.ms在欧美属于常见病,患病率在100～200/10万人.亚洲属于低发区,我国几个小规模的流行病学调查显示患病率在0.88～10/10万人,但是近年来有上升的趋势[1].     

用于多发性硬化症的口服免疫调节剂Laquinimod

多发性硬化症（MS）是一种中枢神经系统（CNS）的炎性脱髓鞘疾病,其特征为局灶性白细胞炎症反应,并导致神经细胞功能障碍、肌无力、视觉障碍以及其他神经损伤症状（如轻度认知障碍、震颤、头晕、失聪、强直、疲劳、触痛、触觉丧失、对温度和疼痛敏感等）。MS的炎症发生在CNS的白质不规则区域,其所致脱髓鞘可减慢或完全阻断神经元传导,疤痕组织的硬化斑块取代髓鞘质,     

The Immune Pathogenesis of Multiple Sclerosis

Multiple sclerosis is an autoimmune disease of the central nervous system (CNS) that leads to changes of nerve conduction due to damage of CNS– resident cells, primarily oligodendrocytes and neurons. CD4+ T cells are of primary importance in the immune cascades leading to tissue damage, but also CD8+ T cells, NK cells and B cells and antibodies contribute to tissue damage. In addition, the innate immune response and mainly microglial cells participate in the events leading to lesions. There are different types of MS and possibly this is due to different underlying immune mechanisms. The current treatment options mainly affect the immune response but have not much influence on secondary signaling changes in astrocytes and neurons which contribute to constant disease progression. The immune response in MS must be seen in the systemic context and there are strong indications that the gut and lung immunity affect MS disease precipitation. The strongest genetic influence in MS is mediated by the HLA class II genes and in Western Europeans and North Americans the disease is associated with HLA–DR2b. Possibly this is due to presentation of a set of specific antigens in context of this HLA allele. Novel data indicates that the immune response in MS is not only focused on certain myelin proteins like myelin basic protein (MBP) but to additional astrocytic and neuronal proteins, which is also mirrored in the pathology. While in the past the disease has been considered as mainly a white matter disease, nowadays it is clear that also grey matter is affected by the aberrant immune response. Still much needs to be learned regarding the underlying events in MS. This expanded knowledge is important to finally discover curative therapies.     

多发性硬化诊疗的进步

多发性硬化(multiple sclerosis,ms)是一种免疫相关性中枢神经系统脱髓鞘疾病.青壮年好发,亚洲国家患病率为(1～10)/10万,而在西方国家高达100/10万.尽管ms发病机制尚未完全清楚,但可以肯定ms是遗传和环境因素共同作用的结果.位于6p21.3位点的hla基因是目前最多证据支持的ms易感基因,占ms基因易感性50%.2007年欧洲、加拿大和美国的ms全基因组扫描首次发现hla基因以外的10余种"小基因",其中包括il7ra、il2ra、cd58等基因,进一步证实ms是多基因疾病.     

儿童多发性硬化的治疗进展

多发性硬化(multiple sclerosis,MS)是以中枢神经系统白质炎性脱髓鞘为主要表现的慢性自身免疫性疾病,是导致年轻患者非创伤性致残最常见的神经系统疾病。2003 年芬兰流行病学调查显示,如未进行有效干预,18~64岁MS患者中完全失去工作能力者可达45%[1] 。2012年全球MS患者已超过210万,2%~10%的MS患者起病于18周岁以前[2-3] 。与成年患者相比,儿童时期起病的MS患者更早出现复发,且复发频率更重,比成人患者平均提前约10年出现躯体残疾。此外,MS患儿可早期出现认知障碍,据报道大约35%的MS患儿诊断时即存在认知功能受损,起病5年内有50%以上的患儿可发生包括语言能力在内的全面认知能力下降[4]。故儿童MS对患儿生活质量与社会医保体系造成巨大影响,如何对MS患儿进行早期及有效干预值得小儿神经病学领域高度关注。     

Immunomodulatory Potential of Methanol Extract of Aegle marmelos in Animals

The aim of the current research was to evaluate the immunomodulatory potential of methanol extract of Aegle marmelos in an experimental animal model of cellular and humoral immunity. Administration of methanol extract of Aegle marmelos (500 and 1000 mg/kg, p.o.) and Ocimum sanctum (100 mg/kg, p.o.), produced significant increase in adhesion of neutrophils and an increase in phagocytic index in carbon clearance assay. Both doses of Aegle marmelos prevented the mortality induced by bovine Pasteurella multocida in mice. Moreover, all treated groups demonstrated significant elevation in circulating antibody titre in the indirect haemagglunation test. From the above results, it can be concluded that methanol extract of Aegle marmelos possess immunomodulatory potential by stimulating cellular and humoral immune mechanisms. However, low dose of methanol extract of Aegle marmelos was more effective for augmenting cellular immunity, whereas, high dose was more inclined towards humoral immunity.     

GEMSP: A New Therapeutic Approach to Multiple Sclerosis

A new therapeutic approach called Endotherapia (GEMSP) for the treatment of Multiple Sclerosis (MS) is suggested. Endotherapia is the result of an immunopathological strategy addressing chronic incurable diseases with a multifactorial etiology. This approach combines a biomedical evaluation of circulating immunoglobulins directed against specific self-antigens and self-antigens modified by free radicals. GEMSP is a "tailor-made" combination of small molecules (fatty acids, antioxidants, radical scavengers, amino acids) linked to a non-immunogenic linear chain of poly-L.lysine (PLL). Each individual linkage or PLL derivative offers great advantages, such as an increase in the half-life of the active small molecules. GEMSP inhibits brain leukocyte infiltration and abolishes episodes of experimental autoimmune encephalomyelitis. In a clinical trial with 102 MS patients treated with GEMSP Endotherapia, 28% of them showed a worsening of their state; 20% showed a decrease in the progression of the disease; 17% showed disease stabilization; and 35% showed a reversal of the evolution of disease; i.e., an improvement in their disease state. In 72% of the cases, a positive evolution of the state of the MS patients treated with Endotherapia was observed (a decrease or stabilization of disease evolution or an improvement). Endotherapia is very safe and no side-effects were reported for GEMSP. Moreover, GEMSP showed no toxicity either in experimental animals or in humans. It seems that Endotherapia is a promising therapy for MS, with no side-effects, which should be considered in the management of long-term pathologies.