Wednesday, 27 May 2015

ClinicSpeak: aspirin for DMF flushing

Does aspirin work for your DMF-related flushing? #ClinicSpeak #MSBlog #MSResearch

"The following study shows that pretreatment (30 minutes before) with aspirin (325mg) reduces the flushing some MSers have when they start DMF (dimethyl fumarate or tecfidera). The response seems to be relatively small, but does provide a pragmatic option in managing this transient side effect. In my experience warning MSers about the flushing and educating them about the transient nature of flushing (usually disappears within 8-12 weeks of starting treatment) seems to help. We have not had many patients stop DMF because of flushing. I think GI symptoms are more problematic than the flushing, in particular the diarrhoea. Any of you want to share your personal experiences?"

Epub: O'Gorman et al. Effect of Aspirin Pretreatment or Slow Dose Titration on Flushing and Gastrointestinal Events in Healthy Volunteers Receiving Delayed-Release Dimethyl Fumarate. Clin Ther. 2015. pii: S0149-2918(15)00188-5. doi: 10.1016/j.clinthera.2015.03.028.

PURPOSE: In Phase III trials, delayed-release dimethyl fumarate (DMF; also known as gastro-resistant DMF) demonstrated significant efficacy and an acceptable safety profile in RRMSers. The purpose of the present study was to examine 2 potential mitigation strategies for flushing and gastrointestinal (GI) events associated with DMF treatment: aspirin (ASA) 325 mg pretreatment for flushing, and slow dose titration of DMF for flushing and GI events.

METHODS: The 8-week study included 173 healthy volunteers randomized to 4 groups; 172 underwent dosing. The placebo group (n = 44) received placebo ASA 30 minutes before placebo DMF (weeks 1-4), then placebo DMF alone (weeks 5-8). The DMF without ASA group (n = 43) and the DMF with ASA group (n = 43) received placebo ASA or ASA, respectively, 30 minutes before DMF (weeks 1-4), then DMF alone (weeks 5-8); in both groups, DMF was dosed at 120 mg BID (week 1) and 240 mg BID (weeks 2-8). The slow dose titration DMF group (n = 42) received DMF 120 mg once daily (week 1), 120 mg BID (week 2), 240 mg in the morning/120 mg in the evening (week 3), and 240 mg BID (weeks 4-8). Subjects recorded information about flushing and GI-related events by using an eDiary and numerical rating scales.

FINDINGS: Flushing and GI-related events were reported in all groups and were mostly rated as mild or moderate in severity. Flushing events were generally ~1 hour in duration and, for most subjects with flushing, initially occurred the first day of study treatment. The duration of GI-related events and time to first GI-related event varied by event type. ASA reduced the incidence, severity, and number of flushing events without affecting duration or time to first flushing event, and had no adverse effect on GI-related events. Dose titration of DMF had no significant effect on flushing or GI events. No subjects discontinued the study due to flushing events. One subject (2%) in the placebo group, 3 subjects (7%) in the DMF without ASA group, 6 subjects (14%) in the DMF with ASA group, and 2 subjects (5%) in the slow dose titration DMF group discontinued treatment because of GI events.

IMPLICATIONS: ASA pretreatment may mitigate flushing associated with DMF, with no adverse effect on GI events. Dose titration of DMF did not have a significant effect on flushing or GI events and is being evaluated further in ongoing clinical trials.

CoI: multiple

Will European Democracy get rid of Animal Research?

Having Democracy allows citizens to protest and within the European Union there are methods to have a debate heard. In the UK a 100,000 signatures in a population of 60 million triggers parliament to discuss the issue. In the European Union you need 1,000,000 signatures out of a population of 500,000,000 to trigger the debate. 

STOP VIVISECTION is a European Citizens' Initiative (ECI) that has collected more than 1.150.000 certified signatures asking people to support a paradigm shift in the way biomedical and toxicological research are being conducted. This is the text of our request which advocates the replacement of animal testing with more accurate, reliable, human-relevant methods:
They say "We urge the European Commission to abrogate directive 2010/63/EU on the protection of animals used for scientific purposes and to present a new proposal that does away with animal experimentation and instead makes compulsory the use - in biomedical and toxicological research - of data directly relevant for the human species".

In the UK animals in research have been protected by Law since 1876 and Directive 2010/63/EU is the directive that protects animals used for science. This brings Europe to a standard that has been enforced in the UK for many years. Abolishing protection of animals in research seems rather retrograde 

This week the European Union had this debate and it seems from probably biased centres that it was a bit dull, Apparently "the claims, that animal models have no predictive value for human disease, drew thin and only occasional ripples of agreement from a cluster of supporters seated at the back of the half-filled aud"itorium.

Apparently The European Parliament has until 3 June 2015 to decide what to do. 

Perhaps it should listen to the loud (Ho-Ho) and unified voice of the continent’s scientists.....and then do precisely nothing, otherwise it may simply cause things to move East and Westwards where less regulation and animals rights are in place.

MS Pharma are already moving.

They are closing or moving their MS research elsewhere maybe to countries where they think it is OK to tie mice upside down by its tail for a month. 

What you you think?....Do you care? ... You Should

It seems you don't have to go too far East to find terrible abuse.
                                              RIP Allan 

Blood cells as a maker of inflammation

Demirci S, Demirci S, Kutluhan S, Koyuncuoglu HR, Yürekli VA. The Clinical Significance of the Neutrophil-to-Lymphocyte Ratio in Multiple Sclerosis. Int J Neurosci. 2015 May 22:1-24. [Epub ahead of print]

Multiple sclerosis (MS) is one of the main chronic inflammatory diseases of the central nervous system that causes functional disability in young people. The aim of this study was to investigate the neutrophil-to-lymphocyte ratio (NLR) in patients with MS and the relationship between the NLR and the severity of the disease. One hundred two MS patients (31 patients were in relapse; 71 patients were in remission) and 56 healthy controls were included. Complete blood counts as well as demographic and clinical data from MS patients were evaluated retrospectively. The NLRs were calculated for all participants and were compared; the cut-off value was also determined for the NLR and Expanded Disability Status Scale (EDSS). MS patients had a significantly higher NLR (p < 0.001) than the control group. The NLR levels were significantly higher in patients that were in relapse than patients in remission (p = 0.039). The cut-off value for the NLR to predict a MS diagnosis and activity were determined to be 2.04 and 3.90 respectively. The NLRs were directly correlated with erythrocyte sedimentation rate (ESR) levels (r = 0.795, p < 0.001). Logistic regression analysis with dichotomous EDSS score showed that a high NLR was an independent predictor of the progression of disability. The NLR may be a biomarker that has simple, quick, inexpensive, and reproducible properties in MS to predict patient's prognosis.

Neutrophil granulocytes (also known as neutrophils) are the most abundant (40% to 75%) type of white blood cells in mammals and form an essential part of the innate immune system. They are short-lived and highly motile. The name neutrophil derives from staining characteristics on hematoxylin and eosin (H&E) histological or cytological preparations. Whereas basophilic white blood cells stain dark blue and eosinophilic white blood cells stain bright red, neutrophils stain a neutral pink. Normally, neutrophils contain a nucleus divided into 2–5 lobes.

Neutrophils are a type of phagocyte and are normally found in the bloodstream. During the beginning (acute) phase of inflammation, particularly as a result of bacterial infection, environmental exposure, and some cancers, neutrophils are one of the first-responders of inflammatory cells to migrate towards the site of inflammation. They migrate through the blood vessels, then through interstitial tissue, following chemical signals such as Interleukin-8 (IL-8), C5a, fMLP and Leukotriene B4 in a process called chemotaxis. They are the predominant cells in pus, accounting for its whitish/yellowish appearance.Neutrophils are recruited to the site of injury within minutes following trauma, and are the hallmark of acute inflammation.

MS is considered to be chronic inflammation and are rare in MSand are also a rare in EAE,that is unless its mouse EAE. I has been suggested that Th17 T cells can induce EAE has lots of neutrophils and if you look in some mouse strains, neutrophils can make up about 80% of the white cells. Neutrophils are common in mouse inflammatory skin lesions and are rare in rats lesions and guinea pig skin lesions. its a mouse thing. But because of neutrophils in mouse and so some people think that they are important in MS and maybe they are, but it is important that we look at MS,rather than make MS mouse EAE. Neutrophils are more common in neuromyelitis optica lesions

In this study they look at the neutrophil to lymphocyte ratio (NLR) and find that it is elevated in MS and active MS. However the NLR is used as a marker of subclinical inflammation and occurs in a number of conditionsBlood nu