Placebo

Statins, among the most commonly prescribed drugs worldwide, are cholesterol-lowering agents used to manage and prevent cardiovascular and coronary heart diseases. Recently, a multifaceted action in different physiological and pathological conditions has been also proposed for statins, beyond anti-inflammation and neuroprotection. Statins have been shown to act through cholesterol-dependent and -independent mechanisms and are able to affect several tissue functions and modulate specific signal transduction pathways that could account for statin pleiotropic effects. Typically, statins are prescribed in middle-aged or elderly patients in a therapeutic regimen covering a long life span during which metabolic processes, aging, and concomitant novel diseases, including cancer, could occur. In this context, safety, toxicity, interaction with other drugs, and the state of health have to be taken into account in subjects treated with statins. Some evidence has shown a dichotomous effect of statins with either cancer-inhibiting or -promoting effects. To date, clinical trials failed to demonstrate a reduced cancer occurrence in statin users and no sufficient data are available to define the long-term effects of statin use over a period of 10 years. Moreover, results from clinical trials performed to evaluate the therapeutic efficacy of statins in cancer did not suggest statin use as chemotherapeutic or adjuvant agents. Here, we reviewed the pharmacology of the statins, providing a comprehensive update of the current knowledge of their effects on tissues, biological processes, and pathological conditions, and we dissected the disappointing evidence on the possible future use of statin-based drugs in cancer therapy.

Pharmacological Actions of Statins: A Critical Appraisal in the Management of Cancer

https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(13)62242-4.pdf

Effect of high-dose simvastatin on brain atrophy and disability in secondary progressive multiple sclerosis (MS-STAT): a randomised, placebo-controlled, phase 2 trial.

The Canadian Multiple Sclerosis Working Group (CMSWG) developed practical recommendations in 2004 to assist clinicians in optimizing the use of disease-modifying therapies (DMT) in patients with relapsing multiple sclerosis. The CMSWG convened to review how disease activity is assessed, propose a more current approach for assessing suboptimal response, and to suggest a scheme for switching or escalating treatment. Practical criteria for relapses, Expanded Disability Status Scale (EDSS) progression and MRI were developed to classify the clinical level of concern as Low, Medium and High. The group concluded that a change in treatment may be considered in any RRMS patient if there is a high level of concern in any one domain (relapses, progression or MRI), a medium level of concern in any two domains, or a low level of concern in all three domains. These recommendations for assessing treatment response should assist clinicians in making more rational choices in their management of relapsing MS patients.

/pdf/treatment-optimization-in-ms-canadian-ms-working-group-3ogmkdmwwb.pdf

Treatment optimization in MS: Canadian MS Working Group updated recommendations.

Multifunctional compounds: smart molecules for multifactorial diseases.

Background
Inspiratory muscle weakness has been observed in patients with stroke. Inspiratory muscle training is an intervention that has shown possible effects for functional recovery of patients with stroke.

Objectives
To investigate the effect and safety of inspiratory muscle training for improving activities of daily living, respiratory muscle function, quality of life and cardiorespiratory fitness after stroke.

Search methods
We searched the Cochrane Stroke Group's Trials Register (August 2011), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011, October Issue 4), MEDLINE (1948 to October 2011), EMBASE (1974 to October 2011), CINAHL (1982 to October 2011), AMED (1985 to October 2011), PEDro (October 2011) and four Chinese databases. In an effort to identify further published, unpublished and ongoing trials, we searched ongoing trials registers and conference proceedings, checked reference lists, and contacted authors of relevant studies and training devices manufactures. There were no language restrictions.

Selection criteria
Randomised controlled trials (RCTs) comparing inspiratory muscle training with no intervention, sham inspiratory muscle training or other cardiorespiratory training for patients with stroke were eligible.

Data collection and analysis
Two review authors independently assessed trial quality and extracted data. The primary outcomes were activities of daily living and respiratory muscle strength; the secondary outcomes were quality of life, cardiorespiratory fitness and adverse effects.

Main results
We included two trials involving a total of 66 patients in this review. Pooling analyses of data was not possible due to considerable heterogeneity between the trials and a lack of data in both trials. One study found a significant increase in respiratory muscle strength favouring inspiratory muscle training over sham inspiratory muscle training, but there was no significant difference between groups on quality of life. The other study showed that patients receiving inspiratory muscle training were more likely to improve their activities of daily living, quality of life and cardiorespiratory fitness than those patients who received no intervention. However, the main results were not compared directly with breathing retraining. Furthermore, neither of the trials assessed the safety and tolerance of inspiratory muscle training.

Authors' conclusions
There is insufficient evidence to support inspiratory muscle training as an effective treatment to improve function after stroke, and no evidence relating to the safety of inspiratory muscle training. Further well-designed RCTs are required.

/pdf/inspiratory-muscle-training-for-the-recovery-of-function-39sn01a06d.pdf

Inspiratory muscle training for the recovery of function after stroke

Background
Multiple sclerosis (MS) is an inflammatory demyelinating disease of the human central nervous system. Statins, prescribed as cholesterol lowering agents, have shown possible effects for treating MS in experimental and preliminary clinical studies.

Objectives
To evaluate the efficacy and safety of statins administered alone or as add-on to approved treatments for MS.

Search methods
The Trials Search Coordinator searched the Cochrane MS Group Trials Register (1 August 2011). We searched the Chinese National Knowledge Infrastructure (CNKI) (1979 to 1 August 2011), trials registers and conference proceedings. Pharmaceutical companies and authors of included studies were contacted for additional information.There were no language restrictions.

Selection criteria
Randomised controlled trials comparing statins with placebo, or comparing statins in combination with approved treatments alone for patients with MS.

Data collection and analysis
Three review authors independently assessed trial quality and extracted data.

Main results
Four trials involving 458 participants were included. All trials compared statins (two evaluating atorvastatin and two simvastatin) plus interferon beta-1a with interferon beta-1a alone for treating MS. The methodological quality was good for three studies and poor for remaining one. None of them showed statistically significant difference between both treatment groups in reducing relapses, preventing disease progression or developing new T2 or gadolinium-enhanced lesions on MRI after 9, 12, 24 months follow up period. Statins resulted to be safe and well tolerated, no serious adverse effects were reported. Changes on quality of life after receiving statins were not reported in the trials.

Authors' conclusions
There is no convincing evidence to support the use of either atorvastatin or simvastatin as an adjunctive therapy in MS.

/pdf/statins-for-multiple-sclerosis-15cppcr00j.pdf

Statins for multiple sclerosis

Background
Parkinson's disease is one of the most common neurodegenerative disorders and mitochondrial dysfunction plays an important role in its pathogenesis. Creatine is effective in improving mitochondrial function. It may therefore be useful for slowing the progression of Parkinson's disease.

Objectives
To assess the efficacy and safety of creatine used alone or as an adjuvant treatment for Parkinson's disease.

Search methods
We searched the Cochrane Movement Disorders Group Trials Register, CENTRAL (The Cochrane Library 2013, November Issue 4), MEDLINE (January 1966 to 10 November 2013), EMBASE (1974 to 10 November 2013) and two Chinese databases. We searched ongoing trials registers and conference proceedings, checked reference lists and contacted authors of included trials.

Selection criteria
Randomized controlled trials (RCTs) comparing creatine versus placebo for Parkinson's disease.

Data collection and analysis
Two review authors independently selected the trials for inclusion, assessed trial quality and extracted data.

Main results
We included two RCTs with a total of 194 patients. Both trials compared creatine with placebo for Parkinson's disease and both had methodological limitations. There was no clear evidence of an effect on motor function (MD -0.26; 95% confidence interval (CI) -4.39 to 3.88, low quality evidence), activities of daily living (MD 0.37; 95% CI -1.28 to 2.02, low quality evidence) or quality of life after one or two years of treatment. One trial reported serious adverse events that were not attributed to creatine. Also, one trial observed higher rates of gastrointestinal effects at two years follow-up.

Authors' conclusions
The evidence base on the effects of creatine in Parkinson's disease is limited by risk of bias, small sample sizes and short duration of the eligible trials. It does not provide a reliable basis on which treatment decisions can be made. Future well-designed RCTs with larger sample size and long-term follow-up are needed to assess creatine for Parkinson's disease.

Creatine for Parkinson's disease

Background Epilepsy is a common neurologic disorder, affecting approximately 50 million people worldwide; nearly a third of these people have epilepsy that is not well controlled by a single antiepileptic drug (AED) and they usually require treatment with a combination of two or more AEDs. In recent years, many newer AEDs have been investigated as add-on therapy for focal epilepsy; losigamone is one of these drugs and is the focus of this systematic review. This is an update of a Cochrane Review first published in 2012 and updated in 2018. Objectives To investigate the efficacy and tolerability of losigamone when used as an add-on therapy for focal epilepsy. Search methods For the latest update on 20 August 2019, we searched the Cochrane Register of Studies (CRS Web) and MEDLINE. CRS Web includes randomized or quasi-randomized, controlled studies from the Specialized Registers of Cochrane Review Groups including Cochrane Epilepsy, CENTRAL, PubMed, Embase, ClinicalTrials.gov, and the World Health Organization International Clinical Trials Registry Platform (ICTRP). Previously we searched trials registers and contacted the manufacturer of losigamone and authors of included studies for additional information. We did not impose any language restrictions. Selection criteria Randomized controlled, add-on studies comparing losigamone with placebo for focal epilepsy. Data collection and analysis Two review authors independently assessed study quality and extracted data. The primary outcomes were 50% or greater reduction in seizure frequency and seizure freedom; the secondary outcomes were treatment withdrawal and adverse events. Results are presented as risk ratios (RRs) with 95% confidence intervals (CIs) or 99% CIs (for the individual listed adverse events to make an allowance for multiple testing). Main results Two studies involving a total of 467 participants, aged over 18 years, were eligible for inclusion. Both studies assessed losigamone 1200 mg/day or 1500 mg/day as an add-on therapy for focal epilepsy. We assessed one study as being of good methodological quality while the other was of uncertain quality. For the efficacy outcomes, results showed that participants taking losigamone were significantly more likely to achieve a 50% or greater reduction in seizure frequency (RR 1.76, 95% CI 1.14 to 2.72; 2 studies, 467 participants; moderate-quality evidence), but associated with a significant increase of treatment withdrawal when compared with those taking placebo (RR 2.16, 95% CI 1.28 to 3.67; 2 studies, 467 participants; moderate-quality evidence). For the tolerability outcomes, results indicated that the proportion of participants who experienced adverse events in the losigamone group was higher than in the placebo group (RR 1.34, 95% CI 1.00 to 1.80; 2 studies, 467 participants; moderate-quality evidence). Dizziness was the only adverse event significantly reported in relation to losigamone (RR 3.82, 99% CI 1.69 to 8.64; 2 studies; 467 participants; moderate-quality evidence). Neither study reported the proportion of participants achieving seizure freedom. A subgroup analysis according to different doses of losigamone showed that a higher dose of losigamone (1500 mg/day) was associated with a greater reduction in seizure frequency than lower doses, but was also associated with more dropouts due to adverse events. Authors' conclusions The results of this review showed that losigamone did reduce seizure frequency but was associated with more treatment withdrawals when used as an add-on therapy for people with focal epilepsy. However, the included studies were of short-term duration and uncertain quality. Future well-designed randomized, double-blind, placebo-controlled studies with a longer-term duration are needed. We did not find any new studies since the last version of this review. We judged the overall quality of the evidence for the outcomes assessed as moderate.

Losigamone add-on therapy for focal epilepsy.

Manganese overexposure can induce neurotoxicity, lead to manganism and result in clinical manifestations similar to those of parkinsonism. However, the underlying molecular mechanism is still unclear. This study demonstrated that MnCl2 induces mitophagy and leads to neurotoxicity by promoting BNIP3-mediated reactive oxygen species (ROS) generation. Human neuroblastoma SH-SY5Y cells were used throughout our experiments. Cell viability was detected by cell proliferation/toxicity test kits. Mitochondrial membrane potential was measured by flow cytometry. ROS generation was detected using a microplate reader. Protein levels were evaluated by Western blot. Transmission electron microscopy was used to evaluate mitochondrial morphology. Co-immunoprecipitation was used to verify the interaction between BNIP3 and LC3. MnCl2 led to loss of mitochondrial membrane potential and apoptosis of SH-SY5Y cells by enhancing expression of BNIP3 and conversion of LC3-I to LC3-II. Moreover, MnCl2 reduced expression of the mitochondrial marker protein TOMM20 and promoted interaction between BNIP3 and LC3. The results also indicated that a decrease in BNIP3 expression reduced the mitochondrial membrane potential loss, attenuated apoptosis and reduced mitochondrial autophagosome formation in SH-SY5Y cells after MnCl2 treatment. Finally, we found that manganese-induced ROS generation could be reversed by the antioxidant N-acetyl cysteine (NAC) or silencing BNIP3 expression. BNIP3 mediates MnCl2-induced mitophagy and neurotoxicity in dopaminergic SH-SY5Y cells through ROS. Thus, BNIP3 contributes to manganese-induced neurotoxicity by functioning as a mitophagy receptor protein.

/pdf/manganese-ii-chloride-leads-to-dopaminergic-neurotoxicity-by-3t87vfgpz6.pdf

Man Luo

Papers

Inspiratory muscle training for the recovery of function after stroke

Statins for multiple sclerosis

Creatine for Parkinson's disease

Losigamone add-on therapy for focal epilepsy.

Manganese (II) chloride leads to dopaminergic neurotoxicity by promoting mitophagy through BNIP3-mediated oxidative stress in SH-SY5Y cells.