Friday, 20 January 2017

#NeuroSpeak: MS Trust's Health Professionals Web Resources

Healthcare professionals working in MS may find the MS Trust's new web resource helpful #NeuroSpeak

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Health Professionals Web Resources
Here at the MS Trust we are always working to ensure that people with MS and the specialist health professionals who support them have access to up-to-date, relevant, accurate and useful information. Recently, we've been working with health professionals to look into the information resources currently used, and where there may be gaps. Many thanks to everyone who has been involved in this project and those who completed our survey.

A few topics emerged that professionals wanted more information on, so we decided to send a reminder about the resources we already provide in those areas. We believe the following resources will prove useful to MS health professionals, and support them in their professional development and in providing quality care to people with MS.
Writing an effective business case
We have recently updated a page on our website about capacity planning and writing a good business case, featuring highlights from our guide to writing an effective business case and our capacity planning tool, which are available in full on request.

Understanding commissioning and funding flows in MS services in England
This is a vastly complex subject, but can be hugely beneficial to understand when making a case for service improvement/development. We've created a straightforward, practical guide to funding flows in MS services in England.

Sharing examples of innovative practice
We have recently put together a resource for health professionals highlighting opportunities to implement change in MS services. Featured on this webpage are a number of examples of innovative practice from MS teams across the UK (and the opportunity to add to this list yourself) and suggestions for small steps you can implement to help take forward the action statements from MS Forward View.

Developing an effective, responsive and efficient relapse service
In the summer of 2016, we sent every MS nurse a copy of our guide Eight steps to improving your relapse service: a guide to best practice for MS specialist nurses, which explained relapses, discussed the clinical management of relapses, and set out our 'eight steps' needed to deliver an effective relapse service. We also hoped that this resource may be useful for other MS health professionals and GPs.
Auditing your service with a user survey
The MS Trust offers all UK MS nurse and therapist teams the chance to use this survey through a free service whereby we take away most of the work involved.  By taking part, you will receive a valuable presentation giving evidence of the benefits of your service to patients along with service users' experiences and suggestions for improvement.

Improving the efficiency of disease modifying drug provision
As part of MS Forward View, we looked at the DMD pathway in MS and investigated how capacity may be created in this area of MS care. This report provides a detailed explanation of the current workload associated with DMDs and how this impacts MS teams, models how this workload may develop in future and where capacity may be freed up in this pathway. 
Improving services for people with advanced MS
Another area of MS services we looked at as part of MS Forward View was care for people with advanced MS. Recently, concerns have arisen that this was an aspect of care that was often difficult for teams to fully implement as demands on MS services in general continue to rise. This report outlines the findings of our work on this area, and our recommendations for how services can better meet the needs of people with advanced MS.  

Other resources you may find useful
We hope you find these resources useful, let us know if you have feedback on any of them – we're keen to hear what you think.   
All the best, 
Health Professionals Programme Team  
Multiple Sclerosis Trust
Spirella Building, Bridge Road, Letchworth Garden City, Hertfordshire, SG6 4ET
Phone: 01462 476700  |  Email:

Irish Medical Pot......You Will You Will You Will.

Crowley D, Collins C, Delargy I, Laird E, Van Hout MC. Irish general practitioner attitudes toward decriminalisation and medical use of cannabis: results from a national survey. Harm Reduct J. 2017; 14(1):4. doi: 10.1186/s12954-016-0129-7.


Governmental debate in Ireland on the de facto decriminalisation of cannabis and legalisation for medical use is ongoing. A cannabis-based medicinal product (Sativex®) has recently been granted market authorisation in Ireland. This unique study aimed to investigate Irish general practitioner (GP) attitudes toward decriminalisation of cannabis and assess levels of support for use of cannabis for therapeutic purposes (CTP).


General practitioners in the Irish College of General Practitioner (ICGP) database were invited to complete an online survey. Anonymous data yielded descriptive statistics (frequencies, percentages) to summarise participant demographic information and agreement with attitudinal statements. Chi-square tests and multi-nominal logistic regression were included.


The response rate was 15% (n = 565) which is similar to other Irish national GP attitudinal surveys. Over half of Irish GPs did not support the decriminalisation of cannabis (56.8%). In terms of gender, a significantly higher proportion of males compared with females (40.6 vs. 15%; p < 0.0001) agreed or strongly agreed with this drug policy approach. A higher percentage of GPs with advanced addiction specialist training (level 2) agreed/strongly agreed that cannabis should be decriminalised (54.1 vs. 31.5%; p = 0.021). Over 80% of both genders supported the view that cannabis use has a significant effect on patients' mental health and increases the risk of schizophrenia (77.3%). Over half of Irish GPs supported the legalisation of cannabis for medical use (58.6%). A higher percentage of those who were level 1-trained (trained in addiction treatment but not to an advanced level) agreed/strongly agreed cannabis should be legalised for medical use (p = 0.003). Over 60% agreed that cannabis can have a role in palliative care, pain management and treatment of multiple sclerosis (MS). In the regression response predicator analysis, females were 66.2% less likely to agree that cannabis should be decriminalised, 42.5% less likely to agree that cannabis should be legalised for medical use and 59.8 and 37.6% less likely to agree that cannabis has a role in palliative care and in the treatment of multiple sclerosis (respectively) than males.


The majority of Irish GPs do not support the present Irish governmental drug policy of decriminalisation of cannabis but do support the legalisation of cannabis for therapeutic purposes. Male GPs and those with higher levels of addiction training are more likely to support a more liberal drug policy approach to cannabis for personal use. A clear majority of GPs expressed significant concerns regarding both the mental and physical health risks of cannabis use. Ongoing research into the health and other effects of drug policy changes on cannabis use is required.

The Dáil (Irish Government) has passed a bill to make cannabis available in Ireland for medicinal use.
The Irish Government had said it would not oppose the legislation.
It aims to legalise and regulate cannabis products used for medical purposes.

What do Doctors think?....Do Doctors think:-)

The title pays homage to "FatherTed" an Irish Comedy about Priests in a Parish on an Island. So there was a survey amongst Irish GPs about whether support decriminalization for therapeutic us of cannabis. In the US there is a growing number of states that support growing for medical consumption, will Ireland so the same way. 

Well it seem they could not give a feck for doing surveys as there was only 15% who replied, but most though decriminalization was not the way to go, most though it could be bad for you, but there was some support for medical use. 

What we have been trying to do is to exploit the benefit that cannabis has to offer, without the side effect so we can create a pharmaceutical medicine and move the science away from the recreational cannabis users

GA...Today's mechanism.

Ahn YH, Jeon SB, Chang CY, Goh EA, Kim SS, Kim HJ, Song J, Park EJ.Glatiramer acetate attenuates the activation of CD4+ T cells by modulating STAT1 and -3 signaling in glia.
Sci Rep. 2017 Jan 17;7:40484

Interactions between immune effector cells of the central nervous system appear to directly or indirectly influence the progress/regression of multiple sclerosis (MS). Here, we report that glial STAT1 and -3 are distinctively phosphorylated following the interaction of activated lymphocytes and glia, and this effect is significantly inhibited by glatiramer acetate (GA), a disease-modifying drug for MS. GA also reduces the activations of STAT1 and -3 by MS-associated stimuli such as IFNγ or LPS in primary glia, but not neurons. Experiments in IFNγ- and IFNγ receptor-deficient mice revealed that GA-induced inhibitions of STAT signaling are independent of IFNγ and its receptor. Interestingly, GA induces the expression levels of suppressor of cytokine signaling-1 and -3, representative negative regulators of STAT signaling in glia. We further found that GA attenuates the LPS-triggered enhancement of IL-2, a highly produced cytokine in patients with active MS, in CD4+ T cells co-cultured with glia, but not in CD4+ T cells alone. Collectively, these results provide that activation of glial STATs is an essential event in the interaction between glia and T cells, which is a possible underlying mechanism of GA action in MS. These findings provide an insight for the development of targeted therapies against MS

Is it really a new mechanism? 

Not really as GA has always been inhibiting T cells hasn't it?

STAT1 and STAT3 are transcription factor i.e. they affect the production levels of proteins from the DNA.

The study says that GA reduces the effect of the STATS in response to  interferon gamma and LPS. LPS is lipopolysaccharide a sugar like molecule on bacteria...So this implies that MS is caused by bacteria!. 

They examine the effect of this case it is usually a mix of microGLIA and astroGLIA but they do experiments in single cell types too.

It states "All animal procedures were performed according to the ARRIVE guidelines". However the ARRIVE guidelines are a reporting guideline, not a how to do experiments guideline.

So it shows how good the referees and editors are:-)

However, is this real?  Why because the glatiramer acetate was from a chemical supply company and not the real McCoy.  So is this generic any good.

COI : None

Thursday, 19 January 2017

#ClinicSpeak & #BrainHealth: online rating sites - good or bad?

Is your MS centre ready for open online reviews? #ClinicSpeak #BrainHealth

For the last year I have been promoting the concept of an msAdvisor for the field to help promote the 'Brain Health: Time Matters' policy document and to get adoption of the MS management principles we are promoting as part of the initiative. Therefore the following perspective piece in this week's NEJM is very timely. It is clear the US healthcare system is way ahead of the game with several online rating sites already established. The article describes some of the many issues linked to online rating sites. My personal opinion is that they need to offer disease-specific ratings. Why? Each disease has specific issues that are unique to that disease. In the case of MS this could for example refer to the use of MRI, or not, to monitor the disease, allowing pwMS access to their own results, etc. I don't want the msAdvisor to be used to 'name and shame' people and centres, but rather as a tool to nudge or encourage the adoption of 'best practice' as defined by peers. The app could also be used to educate and help pwMS self-manage their disease. The tool could also be used as an information resource. The app would have the ability to keep reviews anonymous and for a 'neutral moderator'.

What I would like to hear from you is the msAdvisor an app you would use? Do you think we should develop it? If, yes what content should we include in it?

Vivian Lee. Transparency and Trust — Online Patient Reviews of Physicians. N Engl J Med 2017; 376:197-199.

....... After years of academic debate over the role and value of patient-satisfaction scores and reviews of health care providers,1,2 Yelp, the online powerhouse of documenting customer satisfaction, is forcing the issue. With more than 102 million customer reviews to date, 6% of them in the health care arena, Yelp easily dwarfs longer-standing commercial physician-review sites such as Healthgrades and Vitals....

....... A recent analysis used natural language processing tools to evaluate 17,000 Yelp reviews of 1352 hospitals and showed that they revealed information similar to that covered by 7 of the 11 categories of patient satisfaction included in the Hospital Consumer Assessment of Healthcare Providers and Systems survey (HCAHPS), along with 12 categories not included in the HCAHPS, such as costs, billing, and scheduling......

....... I believe patient reviews and feedback can serve three main goals. First, like the peer-level perspectives on consumer products and services posted on Amazon, TripAdvisor, and Yelp, reviews of physicians or hospitals can help patients make more informed consumer decisions. Publicly available reviews can help address information asymmetry in the health care market and increase patients’ confidence in their own decisions. Collectively, by making clear their preference for higher-performing systems, patients can become a market force driving quality and value in health care.....

...... Second, patient reviews offer clinicians valuable performance feedback for learning and improving, both individually and across a system. Receptivity to performance feedback, which depends heavily on physicians’ acceptance of the data’s validity, facilitates a culture of continuous learning and patient-centeredness......

....... Third, health care systems and physicians who voluntarily share patient-review data visibly foster a spirit of trust with patients and the community. Patient reviews offer the opportunity to improve health care delivery while strengthening the provider–patient relationship......

Digesting Science in Bournemouth

I had the great pleasure of travelling to Bournemouth last weekend to help the Dorset MS Service deliver a Digesting Science event for their families.

The event was held in the incredibly well kitted out MS Society Osborne Centre in local West Parley. I was very impressed at the facilities in this centre and the programme of events that the branch runs to support people with and affected by MS. 

The families that took part enjoyed learning about how MS affects eye-sight, bladder function, walking, how we treat MS and how to prevent MS. The hands on activities were enjoyed by children aged between 5 and 12 years old and the feedback on the event was hugely positive. Thank you to everyone who came along to make the morning such a success.

Special thanks to Rod Slip for having us and Claire Williams and her colleagues from the Dorset MS Team based at Poole Hospital Michelle, Kirsty and Hannah for such great organisation ….and for the cake!

If you would like to host a Digesting Science event, please get in touch: booking (at) The kits can be sent to you free of charge and we can support you to deliver the event in your area.

The next London based Digesting Science event is in Whitechapel on Saturday the 25th March. More information here and how to book. 

Wednesday, 18 January 2017

#ClinicSpeak: DMF and abnormal liver function

Do you know what your last liver function test showed? If not you should. #ClinicSpeak #MSBlog

Do you know what your latest liver function tests showed? If you have MS and are on a DMT you are likely to be having regular blood tests and one of them are LFTs or liver function tests. The paper below highlights that a rare complication  (<1 in 1,000) of dimethyl fumarate (DMF) may be abnormal LFTs. These tend to occur early and be mild and transient and not associated with severe liver injury. 

I personally don't recall seeing this in any of my patients. I thing to point out is that we shouldn't always blame the DMT when we see abnormal LFTs; in my experience they are usually due to another factor, for example excess alcohol intake, concomitant medications or food supplements. In addition, it appears that pwMS can develop autoimmune hepatitis that is a second autoimmune disease. I have seen three such patients, one on interferon-beta, one on glatiramer acetate and another on natalizumab. I have also seen several patients with MS develop viral hepatitis. What we tend to do if we detect abnormal LFTs is to withdraw the drug to see if the results normalise and then rechallenge. If the rechallenge results in the LFTs becoming abnormal then we can be more confident that it is the cause of the problem. 

The message from this post is that you need to engage with your own monitoring; don't be shy to ask about your blood results. 

Muñoz et al. Liver injury associated with dimethyl fumarate in multiple sclerosis patients. Mult Scler. 2017 Jan 1:1352458516688351

BACKGROUND: In pre-approval trials, there was an increased incidence of mild, transient elevations of liver aminotransferases in study subjects treated with dimethyl fumarate (DMF).

OBJECTIVE/METHODS: To evaluate post-marketing cases of drug-induced liver injury associated with DMF.

RESULTS: We identified 14 post-marketing cases of clinically significant liver injury. Findings included newly elevated serum liver aminotransferase and bilirubin levels that developed as early as a few days after the first dose of DMF. The pattern of liver injury was primarily hepatocellular. No cases resulted in liver failure.

CONCLUSION: Health professionals should be alerted to possible serious liver injury in patients receiving DMF.

CoI: multiple

Out of the Frying Pan into the Fire?

Selmaj K, Barkhof F, Belova AN, Wolf C, van den Tweel ER, Oberyé JJ, Mulder R, Egging DF, Koper NP, Cohen JA; GATE study group. Switching from branded to generic glatiramer acetate: 15-month GATE trial extension results.Mult Scler. 2017 Jan 1:1352458516688956.


Open-label 15-month follow-up of the double-blind, placebo-controlled Glatiramer Acetate clinical Trial to assess Equivalence with Copaxone® (GATE) trial.


To evaluate efficacy, safety, and tolerability of prolonged generic glatiramer acetate (GTR) treatment and to evaluate efficacy, safety, and tolerability of switching from brand glatiramer acetate (GA) to GTR treatment.


A total of 729 patients received GTR 20 mg/mL daily. Safety was assessed at months 12, 15, 18, 21, and 24 and Expanded Disability Status Scale and magnetic resonance imaging (MRI) scans at months 12, 18, and 24. The presence of glatiramer anti-drug antibodies (ADAs) was tested at baseline and months 1, 3, 6, 9, 12, 18, and 24.


The mean number of gadolinium-enhancing lesions in the GTR/GTR and GA/GTR groups was similar at months 12, 18, and 24. The change in other MRI parameters was also similar in the GTR/GTR and GA/GTR groups. The annualized relapse rate (ARR) did not differ between the GTR/GTR and GA/GTR groups, 0.21 and 0.24, respectively. The incidence, spectrum, and severity of reported adverse events did not differ between the GTR/GTR and GA/GTR groups. Glatiramer ADA titers were similar in the GTR/GTR and GA/GTR groups.


Efficacy and safety of GTR is maintained over 2 years. Additionally, switching from GA to GTR is safe and well tolerated.

Eventually the Patent Life of Glatiramer acetate has run out, its amazing that the lawyers have kept it going considering that the entity was created in the 1970s.
So whilst Teva has been busy convincing people to switch from once a day injection to thre times a week with abit more, the competitors have been making generic mixes to muscle in of the profits. This study looks at the turn coats that have turned their back on the branded version to go for the generic version because they don't like paying money for cardboard, which is the box it comes in, OK it may not come in carboard but  hope you get the point. That they are the same thing in differnt packaging. However the originals will have it that the genrics are not the same and have done the experiments to show cytokine X or Y responds differntly between the cheap stuff. Anyway proof is in the pudding and so what happens in real life?
In reality nothing happened it was a seamless switch and when you look at the annualised relapse rates of 0.2 (1 releapse every 5 years). I may have to eat some words and say it is not that different from that shown with alemtuzumab in the trials which was 0.18, is it great however when you look at how i think it works then it isn't in the same league as alemtuzumab.
So maybe not out of the pan into the fire but from the badda bing to the bosch-whallop. 

So will you swop?
I guess many will say if it ain't broken don't fix it and brand loyalty is what the companies hope for.

Alemtuzumab inhibits T regs again.

Pant AB, Wang Y, Mielcarz DW, Kasper EJ, Telesford KM, Mishra M, Haque A, Smith J, Kasper LH, Begum-Haque S. Alteration of CD39+Foxp3+ CD4 T cell and cytokine levels in EAE/MS following anti-CD52 treatment. J Neuroimmunol. 2016 Dec 21. pii: S0165-5728(16)30286-7.

While examining the therapeutic value of anti-CD52 antibody against EAE/MS, we identified a unique subset of CD39+ Tregs in repopulating GALT tissues, a major lymphoid reservoir, which was accompanied by amelioration of disease. Furthermore, anti-CD52 treatment leads to increased expression of BDNF, IL-10, and SMAD3 in the brains of EAE mice. This condition is associated with suppression of IL-17, a critical inflammatory factor in EAE/MS progression. Additionally, we found elevated levels of CD4+CD39+ Tregs in PBMCs of RRMS patients treated with humanized anti-CD52 mAb. Thus, anti-CD52 can affect multiple immune mediated pathways involved in the pathogenesis of EAE/MS.

This paper looked and found an increase in a Treg population that goes into the Gut Associated Lymphoid Tissue (GALT). This is reported to increase in MS, so is this a reason why MS goes away?

Time will tell...however are we being sold a curve ball?...

Does it tell us about why alemtuzumab works or does it tell us how alemtuzumab causes autoimmune side effects.

Tuesday, 17 January 2017

Is there chronic blood loss in progressive MS?

Wellcome Open Res. 2016 Nov 15;1:10.

Free serum haemoglobin is associated with brain atrophy in secondary progressive multiple sclerosis.

Lewin A, Hamilton S, Witkover A, Langford P, Nicholas R, Chataway J, Bangham CR.


Background A major cause of disability in secondary progressive multiple sclerosis (SPMS) is progressive brain atrophy, whose pathogenesis is not fully understood. The objective of this study was to identify protein biomarkers of brain atrophy in SPMS. Methods We used surface-enhanced laser desorption-ionization time-of-flight mass spectrometry to carry out an unbiased search for serum proteins whose concentration correlated with the rate of brain atrophy, measured by serial MRI scans over a 2-year period in a well-characterized cohort of 140 patients with SPMS. Protein species were identified by liquid chromatography-electrospray ionization tandem mass spectrometry. Results There was a significant (p<0.004) correlation between the rate of brain atrophy and a rise in the concentration of proteins at 15.1 kDa and 15.9 kDa in the serum. Tandem mass spectrometry identified these proteins as alpha-haemoglobin and beta-haemoglobin, respectively. The abnormal concentration of free serum haemoglobin was confirmed by ELISA (p<0.001). The serum lactate dehydrogenase activity was also highly significantly raised (p<10-12) in patients with secondary progressive multiple sclerosis. Conclusions An underlying low-grade chronic intravascular haemolysis is a potential source of the iron whose deposition along blood vessels in multiple sclerosis plaques contributes to the neurodegeneration and consequent brain atrophy seen in progressive disease. Chelators of free serum iron will be ineffective in preventing this neurodegeneration, because the iron (Fe2+) is chelated by haemoglobin.

This work is performed using the serum samples from the MS-STAT study which showed a small yet significant reduction in the rate of brain volume with high-dose (80mg) simvastatin. The aim of this study was to find potential biomarkers of brain atrophy.

Here, Lewin et al. report a new potential candidate; free serum haemoglobin. It does not come as news to me that this wasn't picked up by other seasoned proteomics researchers before, as it's easy to overlook proteins where there is lack of substantiating evidence in the disease under question. That is, this may be present in previous screens but not flagged as significant by the researchers reporting it! In the same way I'm surprised that neurofilament proteins were not flagged in Lewin's work as I know them to be a consistent finding in sample screens for progressive MS and increased with brain volume loss...

Proteomics also suffers from pre-analytical variations i.e. sample processing, storage etc., which may lead to differential findings from group to group. This is why, a confirmatory check is needed (i.e. the same change is demonstrated by another methodology, for example ELISA), which is what is performed here. They demonstrate that there is a similar rise in serum haemoglobin using commercial test (provided by Abcam). But they do not provide any validation data on this, which is a paramount requirement in this field of research. The European Biomarker Consortium provided a guidance document with regard to reporting on new biomarkers (Guidelines for uniform reporting of body fluid biomarker studies in neurologic disorders. Gnanapavan S, Hegen H, Khalil M, Hemmer B, Franciotta D, Hughes S, Hintzen R, Jeromin A, Havrdova E, Tumani H, Bertolotto A, Comabella M, Frederiksen J, Álvarez-Cermeño JC, Villar L, Galimberti D, Myhr KM, Dujmovic I, Fazekas F, Ionete C, Menge T, Kuhle J, Keir G, Deisenhammer F, Teunissen C, Giovannoni G), to avoid scientists spending time on researching random findings! I suppose it's fine because the authors state that "these results do not suggest that free serum haemoglobin concentration is useful in the differential diagnosis of neurological disease", which is smart!

Let's look at the hypothesis, this is an interesting one and well worth taking a second look. We know that in all neurodegenerative disorders, including MS, there is an increase in the iron deposition in the brain. Normally, there is iron bound to haemoglobin in red blood cells. When you spin blood to obtain the serum the red blood cells (which are heavier) separate out at the bottom of the tube. Therefore, any free blood in the sample, outside of rubbish venepuncture technique (I'm assuming that haemolysed samples were excluded prior to analysis, as this is a requirement for proteomic studies), is indicative of blood break down (or haemolysis). There is then a possibility, that this may cause problems (see above figure for a potential mechanism); although I don't think this is a direct causal evidence for brain atrophy (i.e. may be epiphenomena), as autoimmune haemolytic anaemia (blood disorder which is both genetic and caused by other illnesses) has no reported mention of brain volume loss. Clearly, more work is needed in this area. Moreover, other groups looking at this also need to examine haptoglobin levels, as haptoglobin binds free serum haemoglobin and genetic variations in haptoglobin between individuals has been reported to affect free serum haemoglobin levels.

Finally, there is no observed treatment effect on free serum haemoglobin of high-dose simvastatin. Lewin et al. state "This effect was independent of the beneficial treatment effect of simvastatin, because there was no association between free haemoglobin concentration and simvastatin treatment", they also state "The results presented here show that a rise in the concentration of free haemoglobin in the serum was associated with the rate of brain atrophy in this cohort of patients with SPMS". Are they, therefore, implying that high-dose simvastatin does not in fact lower the likelihood of brain atrophy! Maybe, I'm putting words in their mouth!! Please place me on a direct line to a good statistician!

Monday, 16 January 2017

#ClinicSpeak: have you been taken for a ride by a prostitute called Turmeric?

We need an evidence base to support the use of Turmeric in MS. #ClinicSpeak #MSBlog

So many of my patients have asked what I  think of Turmeric as a treatment for MS and my stock answer has been that there is no class 1 or 2 evidence (randomised controlled trials) to support the claims that it helps people with MS. Nothing has changed except I can now say that there is now no biological evidence that Turmeric has any medicinal effects

The editorial from last week's Nature on a meta-analysis suggests we have all been duped by the chemical properties of the curcumin, the proposed active ingredient in Turmeric. They show that curcumin is a promiscuous compound and interferes with most drug-screening assays, which have led to false claims about its biological effects. It is a molecular prostitute, i.e. binding promiscuously to many proteins and membranes, and giving false signals or faking it.

I would be interested to know how many of you have tried Turmeric for your MS.

Monya Baker. Deceptive curcumin offers cautionary tale for chemists. Nature 541, 144–145 (09 January 2017) doi:10.1038/541144a

Spice extract dupes assays and leads some drug hunters astray.


..... Inside the golden-yellow spice turmeric lurks a chemical deceiver: curcumin, a molecule that is widely touted as having medicinal activity, but which also gives false signals in drug screening tests. For years, chemists have urged caution about curcumin and other compounds that can mislead naive drug hunters.

......  the most comprehensive critical review yet of curcumin — concluding that there’s no evidence it has any specific therapeutic benefits, despite thousands of research papers and more than 120 clinical trials. The scientists hope that their report will prevent further wasted research and alert the unwary to the possibility that chemicals may often show up as ‘hits’ in drug screens, but be unlikely to yield a drug......

...... “Curcumin is a cautionary tale,” says Michael Walters, a medicinal chemist at the University of Minnesota in Minneapolis, and lead author of the review (K. M. Nelson et al. J. Med. Chem.; 2017), published on 11 January......

......  Commonly used drug screens detect whether a chemical latches on to a binding site of a protein implicated in disease — a hint that it may be the starting point for a drug. But some molecules, such as curcumin, seem to show such specific activity when there is none. The molecules may fluoresce naturally, foiling attempts to use fluorescence as a signal of protein binding. They may disrupt cell membranes, duping assays that try to spot drugs targeting specific cell-membrane proteins. And they may surreptitiously degrade into other compounds that have different properties, or contain impurities that have their own biological activity......

...... Chemists call these irritants PAINS (pan-assay interference compounds) — and curcumin is one of the worst.....

...... Misinterpretations feed on themselves, Walters says. Curcumin gets reported as having an effect even if the assay was flawed. “People accept what is in the literature as being correct and then build a hypothesis, even though it doesn’t hold up.” And scientists don’t seem to check the literature to see whether compounds have been flagged as problematic. At least 15 articles on curcumin have been retracted since 2009 and dozens more corrected......

....... But the review shows that getting real answers will be tough, says Bill Zuercher, a chemical biologist at the University of North Carolina at Chapel Hill. “It may very well be the case that curcumin or turmeric extracts do have beneficial effects, but getting to the bottom of that is complex and might be impossible,” he says. Walters isn’t confident that his report will stop poorly conducted research. “The people who should be reading this probably won’t,” he says ......

Nelson et al. The Essential Medicinal Chemistry of Curcumin. J Med Chem. 2017 Jan 11. doi: 10.1021/acs.jmedchem.6b00975.

Curcumin is a constituent (up to ∼5%) of the traditional medicine known as turmeric. Interest in the therapeutic use of turmeric and the relative ease of isolation of curcuminoids has led to their extensive investigation. Curcumin has recently been classified as both a PAINS (pan-assay interference compounds) and an IMPS (invalid metabolic panaceas) candidate. The likely false activity of curcumin in vitro and in vivo has resulted in >120 clinical trials of curcuminoids against several diseases. No double-blinded, placebo controlled clinical trial of curcumin has been successful. This manuscript reviews the essential medicinal chemistry of curcumin and provides evidence that curcumin is an unstable, reactive, nonbioavailable compound and, therefore, a highly improbable lead. On the basis of this in-depth evaluation, potential new directions for research on curcuminoids are discussed.

Sunday, 15 January 2017

#ClinicSpeak & #ResearchSpeak: obesity comes up trumps

How do we stop the adolescent obesity crisis? It is important for MS. #ClinicSpeak #ResearchSpeak 

Adolescent obesity is a risk factor for developing MS. Is it Chicken or Egg? Is obesity simply associated with MS due to another factor or does obesity act in the MS causal pathway. An example of an association would be that its actually low vD levels, or lack of outdoor activity and less sun exposure, that is the causal factor. People who have less outdoor activity tend to be more sedentary and hence more likely to be obese. The risk factor here is less outdoor activity and not the associated obesity. Obesity could be causal if some part of adipose tissue biology interacts with the MS causal pathway. An example of this is could be one of pro-inflammatory mediators that adipose tissue produces, and there are many such mediators, may prime the immune system to develop autoimmunity. In other words if there was less adipose  tissue, and as a result less adipose tissue induced systemic inflammation, then the risk of autoimmunity will drop. 

Another way adipose tissue may interfere with the causal pathway is actually via vD metabolism. Adipose tissue may lower systemic vD levels by consuming vD as part of its metabolism. The low vitamin D level, and not the obesity, that is the risk factor here.

One way to answer the association vs. causation question is to do a randomised controlled trial of a dietary, or pharmacological intervention, which reverses or prevents adolescent obesity, and to see if the intervention reduces the risk of developing MS. This type of trial would be very difficult to do and may actually not be feasible. 

Is there a cheaper, cleverer, way to do randomised-controlled trial to prove causation? Yes, there is a clever way using Mendelian randomization and seeing if the genetic variants that are linked to obesity are risk factors for developing MS. The study below done using people from California registered with the Kaiser Permanente HMO and a replication sample from Sweden showed just that. The investigators constructed a weighted genetic risk score using genetic variants previously established to predict obesity. Subjects with higher genetically-induced obesity scores had a higher risk of developing MS. Although the investigators controlled for birth year, sex, education, smoking status, ancestry, and genetic predictors of MS they clearly couldn't control for other important con-founders that are very relevant to this analysis, for example dietary factors, exercise - in particular out-door activity - and vD levels. Despite this this study does suggest that obesity is probably part of the MS causal pathway and that if we want to reduce the incidence of MS in the population we need to tackle the problem of adolescent obesity. Now that is much easier said than done!

Gianfrancesco et al. Causal Effect of Genetic Variants Associated With Body Mass Index on Multiple Sclerosis Susceptibility. Am J Epidemiol. 2017 Jan 9. doi: 10.1093/aje/kww120.

Background: Multiple sclerosis (MS) is an autoimmune disease with both genetic and environmental risk factors. Recent studies indicate that childhood and adolescent obesity double the risk of MS, but this association may reflect unmeasured confounders rather than causal effects of obesity. 

Methods: We used separate-sample Mendelian randomization to estimate the causal effect of body mass index (BMI) on susceptibility to MS. Using data from non-Hispanic white members of the Kaiser Permanente Medical Care Plan of Northern California (KPNC) (2006-2014; 1,104 cases of MS and 10,536 controls) and a replication data set from Sweden (the Epidemiological Investigation of MS (EIMS) and the Genes and Environment in MS (GEMS) studies, 2005-2013; 5,133 MS cases and 4,718 controls), we constructed a weighted genetic risk score using 97 variants previously established to predict BMI. 

Results: Results were adjusted for birth year, sex, education, smoking status, ancestry, and genetic predictors of MS. Estimates in KPNC and Swedish data sets suggested that higher genetically induced BMI predicted greater susceptibility to MS (odds ratio = 1.13, 95% confidence interval: 1.04, 1.22 for the KPNC sample; odds ratio = 1.09, 95% confidence interval: 1.03, 1.15 for the Swedish sample). 

Conclusions: Although the mechanism remains unclear, to our knowledge, these findings support a causal effect of increased BMI on susceptibility to MS for the first time, and they suggest a role for inflammatory pathways that characterize both obesity and the MS disease process.

No Evidence of Disease activity with daclizumab

#Clinical Speak. Where to position daclizumab

#AchillesHealSpeak.Is MS a Tcell issue

Kappos L, Havrdova E, Giovannoni G, Khatri BO, Gauthier SA, Greenberg SJ, You X, Wang P, Giannattasio G. No evidence of disease activity in patients receiving daclizumab versus intramuscular interferon beta-1a for relapsing-remitting multiple sclerosis in the DECIDE study. Mult Scler. 2016 Dec 1:1352458516683266.


No evidence of disease activity (NEDA) is a composite endpoint being increasingly applied as an outcome measure in clinical trials as well as proposed for individual therapeutic decisions in multiple sclerosis (MS).


Assess the proportion of patients with relapsing-remitting MS achieving NEDA in the DECIDE study of daclizumab 150 mg subcutaneous versus intramuscular interferon beta-1a 30 µg for 96-144 weeks.


NEDA was defined as no relapses, no onset of 12-week confirmed disability progression (CDP), no new/newly enlarging T2 hyperintense lesions (NET2), and no gadolinium-enhancing (Gd+) lesions. Logistic regression models adjusted for baseline covariates compared treatment groups for baseline to week 96, weeks 0-24, and weeks 24-96.


From baseline to week 96, more daclizumab versus intramuscular interferon beta-1a patients achieved NEDA (24.6% vs 14.2%; odds ratio (OR; 95% confidence interval): 2.059 (1.592-2.661); p < 0.0001). ORs for clinical NEDA (no relapses, no CDP) and magnetic resonance imaging (MRI) NEDA (no NET2, no Gd+ lesions) were 1.651 (1.357-2.007; p < 0.0001) and 2.051 (1.628-2.582; p < 0.0001), respectively. ORs in favor of daclizumab for weeks 24-96 were consistently higher than for weeks 0-24.


More daclizumab versus intramuscular interferon beta-1a patients achieved NEDA early in DECIDE, with effects increasing over time.

Here is one for ProfG to do as he is a coauthor of the paper, he may have an answer and maybe this is going to be something that he will have to wrestle with, that is if NICE approve the treatment. I suspect they will after abit of haggling over price.  

But the big question is going to be where is this drug going to be positioned?

Based on its effect on relapses it is in the moderately effective treatments and is injected every month. Looking at the rate of NEDA, it is better than beta interferon but a long way behind the highly effective agents.  

There is a risk of skin reactions with this agents and in a few percent of cases it can be quite severe. Maybe this is because it depletes T reg cells because they express CD25 and daclizumab blocks CD25. 

This is the high affinity interleukin-2 (T cell growth factor). 
Does this work because it blocks activated T cells which express the IL-2 receptor? This was surely the logic for trying it because if they knew about Tregs then surely T cell immunologists would not have attempted to use it.

Block Tregs and MS should get worse if we follow the dogma, because T regs block autoimmunnity. This the dogma and something that must make the T cell brigade wiggle
Surely MrT will agree with this. 

Maybe MrT will give the doesn't deplete Tregs enough for it to be important. Maybe the job of the Treg is to stop autoimmunity occuring in the first place, but once immunity has been intitiated they don't do much?

However, it doesn,t make MS worse so again what does this say about T cells causing MS? 

However when you block the CD25 the circulating levels of IL-2 increase this binds to the intermediate affintiy interleukin 2 receptor and this is expressed on natural killer cells and so they expand. Natural killer cells are a type of immune cells involved in killing cancers and infections. So is this how daclizumab works, by being more anti-viral?  So is this saying that there is a virus linked to MS?

Is it working some other way than T cells, this agent has to tell us something about MS because after all it is doing something.

The big dilema is how to position this drug? 
It has efficacy of some first line drugs, but side effect that may lead to second line (being too expensive normally guarentees this with NICE). 
How do the companies marketing the drug, position the drug? As they have 
loads in their stable.

Not being a clinician I don't have to conudrm

CoI Prof G is author