[Sciences/Stroke] PCSK9-FOURIER trial and why newer drug is not always better

You may have heard about the FOURIER trial making the news…..or maybe not. What you have maybe heard was this new published clinical trial that has created a divide in the news: In one hand it sounds evolocumab (a PCSK9 inhibitor) is the next cholesterol lowering blockbuster that would put statins into the category of “old drugs”, in the other hand it was raised how this new treatment provide little benefits for a hefty added price ($14’100/year price tag according to this article) compared to statins ($1’409/year price tag for a branded form).

So what is about this study, how does it fare and does it really have such a beneficial value that worth paying the extra $$$? Lets go through together. For this post, I will base my comments on two articles: the FOURIER clinical trial  (Ray, Landmesser et al. 2017) and a recent meta-analysis on the benefits of statins on cardiovascular events (Chou, Dana et al. 2016) .

How does statins and PCSK9 work?

You have heard about statins as a cholesterol-lowering drug, heard about the LDL/HDL ratio with one being “bad” (LDL) and the other being “good” (HDL). Cholesterol is part of our normal functioning. We need cholesterol for our cells and our tissues. Cholesterol is an important component of our cell membrane allowing it to have a certain “fluidity”. Cholesterol is also the precursor of any steroid hormones and it is the source for essential groups of steroid hormones such as glucocorticoids (anti-inflammatory), mineralocorticoids (blood pressure), androgens (male sexual hormones) or estrogens (female sexual hormones).

Cholesterol can come from two sources: diet (by consuming animal products) and by de novo synthesis by the liver from acetyl-coenzyme A (acetyl-coA, through a very long and complex biochemical pathway).


Our liver can produce the amount of cholesterol we need daily, therefore the cholesterol obtained from the diet is an extra amount that is pooled with our endogenous cholesterol. Cholesterol is a fatty acid, it is a lipophilic compound (like fat) that is poorly dissolving in water. One biological adaptation in our evolution was to combine these cholesterol on some proteins called “lipoproteins”, allowing cholesterol to piggy-back and therefore be “soluble” in blood and in interstitial fluids. You have different flavors of these “lipoproteins” based on their physico-chemical properties as observed by ultra-centrifugation. We have the light form called “low-density lipoproteins” (LDL) and the heavier form called “high-density lipoproteins” (HDL).


LDLs are taken up by cells through a particular receptor called “LDL receptors” (LDLR). These receptors are expressed on the cell surface, in particular by liver cells and endothelial cells (cell lining the inner side of blood vessels). LDLs are the one found mostly in atherosclerotic plaques that are responsible for myocardial infarction (MI or heart attack) and cerebral ischemia (ischemic stroke).

Therefore, it is important to keep these LDL levels within normal range. You have two possible actions: either you reduce your dietary intake and/or use medication aimed to block the endogenous cholesterol production.

This is where statins and PCSK9 inhibitors come into action.
Statins target the enzyme called HMG-coA reductase that is involved in the early step of cholesterol biosynthesis.

Proprotein convertase substilisin/kexin 9 (PSCK9) inhibitors in the other hand block the interaction of PSCK9 with LDLRs. PSCK9 is produced by most of our cells and have an affinity to LDLRs. Therefore PCSK9 can compete with LDL for binding to LDLRs and therefore increase the amount of circulating LDL. Worse, once bound to its receptor, PCSK9 forces the internalization of LDLR and block its recycling, further accentuating the amount of circulating LDLs. By blocking PCSK9 ability to bind to LDLR, you can free more LDLR to bind circulating LDLs and therefore decrease your LDL levels.

What is evolocumab?

One compound have been approved by the FDA in this matter, its name is evolocumab (Repatha®, Amgen). It is a biologic, an antibody that will bind to PCSK9 and impeach its binding to LDLR. Because it is a biologic, it is very expensive to produce because it is a high molecular weight protein that cannot be synthesized by chemistry. We have genetically-modified yeasts or mammalian cells that know how to synthesize it if you give them the right gene. Yet, synthesis is only one problem solved, the other problem is protein folding.
It is like an origami folding, a very tortuous and complicated series of step to achieve a desired shape. Like an origami, fail to properly fold and you will have a far cry of a desired finished product.
Yeast and mammalian cells may not fully be efficient at this task and therefore you have to deal with small amount of biologically active product at the end of the manufacturing process. Evolocumab has been approved by the FDA in 2015 for the use in people that cannot use statins and that failed to control their cholesterol levels by dietary intervention. Because it showed interesting outcomes, it was tempting to consider the added benefit of this biologic over statins. We have a good idea on statins risks and benefits and one major advantage of statins are their price. We have generic forms that are very cheap, much more cheaper than evolocumab (at least 10 times cheaper, considering the full price before coupons and insurance plans).

The FOURIER trial
This is the clinical trial that is at the epicenter of the news. In this trial, they assess how evolocumab (EVO) stood against statins and possibility outperformed statins. Statins have been shown their added benefits for patients with high cholesterol compared to placebo treated.

Because it is unethical to assess EVO versus non-treated individuals, you have to compare groups taking their statins with EVO versus groups taking their statins without (refered here as placebo). This is also a method to show that EVO outperforms statins.

We have two groups of reasonable sample sizes: EVO (N=13’784) and placebo (N=13’780) with matched parameters (age, sex, ethnicity, condition, medication……) to ensure the effect you observe are mostly due to EVO and nothing else.
The striking data here is the lowering of the LDL. In placebo, this level is about 90 mg/dL. In EVO group, we are going down to 30mg/L. That’s fairly impressive. But at the end, you want to see the outcome right?

In our case, our outcomes are how many cases of heart attack and stroke we are dealing with.

This is were the results are becoming more contrasted and less exciting.
If we look at secondary endpoint (death by cardiovascular event, heart attack or stroke), EVO fared a bit better than placebo (5.9% versus 7.4%).

For 2000 persons suffering, EVO saved the life of one person death by cardiovascular death. For 200 patients, it saved one person from an heart attack and one person to stroke injury compared to placebo (statins) group.

Considering the possible side effects reported to the medication, the lack of pharmacovigilance and foremost the price of the drug, you have to weight the benefits over risk and costs. This is where things are less shiny. This study fails to show us how EVO will replace statins.

Statins are the devil we know, they are doing their job well, we know their risks and associated side effects fairly well and they are very affordable. EVO is certainly great for patients that cannot rely on statins to control their cholesterol. But the benefit of EVO over statin is marginal and not worth the risk and costs.

Chou, R., T. Dana, I. Blazina, M. Daeges and T. L. Jeanne (2016). “Statins for Prevention of Cardiovascular Disease in Adults: Evidence Report and Systematic Review for the US Preventive Services Task Force.” JAMA 316(19): 2008-2024.

Ray, K. K., U. Landmesser, L. A. Leiter, D. Kallend, R. Dufour, M. Karakas, T. Hall, R. P. Troquay, T. Turner, F. L. Visseren, P. Wijngaard, R. S. Wright and J. J. Kastelein (2017). “Inclisiran in Patients at High Cardiovascular Risk with Elevated LDL Cholesterol.” N Engl J Med.


[Science/Stem Cells] Stem Cell Therapy and Age-related Macular Degeneration – A Tale of Two Cases Reports

Yesterday, a breaking news in the stem cell field came from a case report published in the New England Journal of Medicine (a respected journal in medical research) (http://www.nejm.org/doi/full/10.1056/NEJMoa1609583?query=featured_home).
What is probably the most intriguing about this case report from a stem cell clinic, that had a clinical trial submitted to the FDA and subsequently withdrawn in 2015 (https://clinicaltrials.gov/ct2/show/NCT02024269?term=NCT02024269&rank=1).
This case report focuses on three patients, elderly patients (70+) and all three suffering from age-related macular degeneration (AMD).
They all three being injected with mesenchymal stem cells. For those not familiar with stem cells, stem cells comes into different flavors depending on their origin and potency abilities. The most pluripotent type of stem cells are the embryonic stem cells (hESCs) that are derived from embryos. Following in their pluripotency comes in the induced pluripotent stem cells (iPSCs). Unlike hESCs, iPSCs are reprogrammed somatic cells (usually skin fibroblasts). Then we have bone marrow stem cells (from bone marrow) that have a narrower pluripotency but proven efficacious for treating patients with leukemia. Finally we have the mesenchymal stem cells (MSCs) obtained from the stream fraction of adipose tissue. Usually these cells are obtained by liposuction and isolated from the fat tissue via defined protocols.
Now this last type of cells has a certain classification that allows to use a loophole. In order to conduct a clinical trial, you have to submit an investigative new drug (IND) application to the Food & Drug Administration to show evidence of safety and efficacy from pre-clinical studies. These are safeguards that ensure patients and medical researchers enrolled in such trials.
Now, when you are dealing with MSCs, these stem cell “clinics” can exploit some loopholes and apply for a non-IND application if your trial follows two criteria: it is an autologous procedure (you are injecting cells from yourself back into your body) and there is no procedures that modify the material used (in that case, the purification steps are not altering the MSCs identity and function).  In addition, these trials have to be done without any financial link. In academic institutions, you neither ask the patient to pay for the clinical trial nor  provide the patient with a financial compensation (only a possible therapeutic outcome, if the treatment work). In this case reports, all patients paid $5000 to that clinic. it is also important to note a certain level of deception from the stem cell clinic as this registration at the ClinicalTrials.gov website appeared to these patients as a clinical trial were it was not. It is even mentioned by the authors of this case report that none of the consent form signed by these patients displayed “clinical trial”.
There is also report in the consent form that the patient were informed of the risk of blindness and were requesting to have the procedure done in both eyes.
These patients rapidly developed post-operative complication including retinal detachment, increased ocular pressure and hemorrhagic events, such complications were not taken care by the clinic involved in the stem cell procedure and were done in eye clinics in patients domicile.

By coincidence, NEJM also published another case report of the use of stem cells in AMD in a clinical trial in Japan (http://www.nejm.org/doi/full/10.1056/NEJMoa1608368?query=featured_home). This procedure was done using iPSCs from patients and derived into retinal pigmented epithelial cells (RPEs). These cells are lining the outer side of the retina and serve as a barrier for protecting the retinal neurons involved in vision. This is the famous “iPSC clinical trial” from Takahashi and colleagues that had to be halted due to some safety issues that were corrected (https://ipscell.com/2016/06/good-stem-cell-news-as-takahashi-ips-cell-trial-to-resume/).
So far, the encouraging part is the absence of post-operative complication and graft rejection and the patient showed an improvement in her vision.Yet, this is a single report and the authors were also very cautious about to make overstating conclusion.

These two cases report should inform into two things: we are making little steps but confident steps in stem cell based therapies but it is also important to raise awareness and vigilance about the methods of some stem cell clinics making unrealistic claims of stem cell therapies or posing as clinical trial center.

My recommendation is if you decide to jump into a clinical trial is to verify the affiliation of the center (avoid any private firms and check the credentials of any institution supporting this trial), ask your doctor to help you read through the consent form and never ever be asked to pay for the procedure. The trial is funded by research grants, if it is requested that you cover the expenses of such procedures run away!


[Neurosciences/Alzheimer] Structural variation in amyloid-β fibrils from Alzheimer’s disease clinical subtypes

Interesting study published in Nature about how differences in Abeta fibrils have an implication on the clinical symptoms.
A quick refresher for those not much familiar (it is also a bit of a headache as I just dive in the Alzheimer’s research). Alzheimer’s disease is characterized by the formation of senile plaques and tangles, such structures have been considered as the causative agents in neuronal cell death.
These plaques are clumps of a peptide called Abeta (for amyloid beta) peptides. We know how these peptides are formed (by cleavage of the amyloid precursor protein or APP) and we know there are different “flavors” of Abeta that have been described: Abeta 1-40, Abeta 1-42…..
We also know that these peptides are “sticky”. They are released as monomers (single peptide) and because they are hydrophobic (hates water, like oil hates water) they will try to bind together and form oligomers (think about little sticky balls). These oligomers then can form fibrils.
It is a very “dry” study because it is heavy on structural biology and computational biology but in the same time very interesting.
It shows us that plaque formation is not a linear processes, there are different combinations possible (imagine like comparing snowflakes) that have a direct impact on the clinical presentation and outcomes in patients.
That’s maybe providing another way of thinking in targeting Abeta that can help us learn from the failure of previous clinical trials.

Abstract and link to the original paper

Aggregation of amyloid-β peptides into fibrils or other self-assembled states is central to the pathogenesis of Alzheimer’s disease. Fibrils formed in vitro by 40- and 42-residue amyloid-β peptides (Aβ40 and Aβ42) are polymorphic, with variations in molecular structure that depend on fibril growth conditions. Recent experiments suggest that variations in amyloid-β fibril structure in vivo may correlate with variations in Alzheimer’s disease phenotype, in analogy to distinct prion strains that are associated with different clinical and pathological phenotypes. Here we investigate correlations between structural variation and Alzheimer’s disease phenotype using solid-state nuclear magnetic resonance (ssNMR) measurements on Aβ40 and Aβ42 fibrils prepared by seeded growth from extracts of Alzheimer’s disease brain cortex. We compared two atypical Alzheimer’s disease clinical subtypes—the rapidly progressive form (r-AD) and the posterior cortical atrophy variant (PCA-AD)—with a typical prolonged-duration form (t-AD). On the basis of ssNMR data from 37 cortical tissue samples from 18 individuals, we find that a single Aβ40 fibril structure is most abundant in samples from patients with t-AD and PCA-AD, whereas Aβ40 fibrils from r-AD samples exhibit a significantly greater proportion of additional structures. Data for Aβ42 fibrils indicate structural heterogeneity in most samples from all patient categories, with at least two prevalent structures. These results demonstrate the existence of a specific predominant Aβ40 fibril structure in t-AD and PCA-AD, suggest that r-AD may relate to additional fibril structures and indicate that there is a qualitative difference between Aβ40 and Aβ42 aggregates in the brain tissue of patients with Alzheimer’s disease.

Source: Structural variation in amyloid-β fibrils from Alzheimer’s disease clinical subtypes : Nature : Nature Research

[Sciences/BBB] Histamine-induced blood-brain barrier disruption in teething children: a “post hoc ergo” on glucocorticoids.

Recently, I have been aware about some parents concerned about the impact of teething on the blood-brain barrier integrity, such claims was wrapped through one of the most bizarre “ergo post hoc” fallacy following that sequence:
1. Teething induces histamine release
2. Histamine is a vascular hyperpermeable vascular factor
3. Blood-brain barrier in babies is leak
4. Therefore Teething induces a blood-brain barrier breakdown in children.

You have to agree that is one of the most bizarre fallacious association, but it has been repeated and spread enough to have parents concerned about the impact of teething on the blood-brain barrier. To dispel that myth and beat that dead horse once for all, I think it is important to demonstrate why this information is fallacious.


  1. Teething and histamine release: understanding the mechanism of inflammation.

First, in order to understand the physiological response of teething, you have to understand the mechanism of inflammation. Everyone can provide a clinical presentation of an inflammation: it is red, it is swollen and it is hot.
Inflammation is triggered by lesion or a wound due to internal or external stimuli, in our case teething. Teething involves a mechanical stress (due to teeth growth) and eventually cells and tissue laceration. Such laceration release intracellular contents into the extracellular space that turns on resident immune cells. These cells in turn release what we refer to “pro-inflammatory factors”, a cocktail of different chemicals that triggers the inflammatory bomb on:

We have amino-acids derivatives and peptides (bradykinin, histamine, inflammatory chemokines and cytokines) and arachidonic acid (AA)-derived molecules. The production of AA-derived molecules (also known as prostanoids) are driven by cyclo-oxygenases (COXs). There are two types of COXs: COX1 that is constantly produced at small level and COX2 that is increased during inflammation.  COX1 produce the “good prostanoids” and COX2 the “bad prostanoids”, the latter being the driving force of the inflammation. COXs are the classical targets of the classical NSAIDs found in OTC products including acetaminophen (Tylenol), ibuprofen (Advil) and naproxen (Aleve). All these small molecule target COXs and stop prostanoids production. In the case of teething, inflammation is mostly driven by the release of prostanoids (such as prostaglandin PGE2) and interleukins (IL-1beta) (Blakey, White et al. 1996). Aside of two obscure studies published 40 years ago in obscure medical journals (Cotias, de Medeiros et al. 1968, Soliman, Abdel Wahed et al. 1977) there is no evidence of histamine release following teething. This therefore nullify claim 1.

  1. Histamine and the blood-brain barrier

Histamine is not the major mediator of inflammation, but it is indeed the major mediator in allergic reaction. During an allergic reaction, the immune system respond to the allergen by the production of certain types of antibodies called IgE.

IgE are produced by B-cells that positively responded to the allergen, recognizing it as a foreign body. IgE binds to a certain type of immune cells called mast cells. Mast cells are about less than 1% of the total population of immune cells. These cells are super-loaded with histamine, ready to puff it upon signal. Once IgE binds to its appropriate receptor, mast cells puff and release vast amount of histamine. Histamine in turns triggers the anaphylactic response such as “asthma”, “runny nose” and in the worst case an anaphylactic shock. The main treatment for mild allergic reaction is solved by taking anti-histaminic drugs such as Claritin D or Benadryl.
Because the histamine released in teething is much more negligible than the amount of prostanoids produced, the use of anti-histaminic is worthless because you only address a minor component of the inflammation and omit to block the major component. So the histamine relationship with teething is also refuted at this point. But does histamine can cause the BBB disruption and its leakiness? Yes, but only at high doses and only in very specific cases. Studies that have investigated the biological effects of histamine at the BBB are very old (20+ years) and were achieved with high concentrations (10-100 micromol/L) (Gross, Teasdale et al. 1981, Domer, Boertje et al. 1983, Watanabe and Rosenblum 1987, Butt and Jones 1992, Mayhan 1996). If we consider that histamine is produced during teething, we can conservatively assume that such level would not be over plasma levels found during a severe allergic reaction such as an anaphylactic shock. Reported values for an anaphylactic shock are about 6.35 nmol/L (Laroche, Gomis et al. 2014). Even at that high level, that’s put us about 1000X to 16000X less than values reported to have an activity on the BBB. So claim 2 is also refuted.

  1. Is the BBB leaky in newborns and babies?

TL; DR the short answer is NO. If you want to understand why and what is the science behind my statement, please check my previous post about it: https://scientistabe.wordpress.com/2016/05/21/neurosciencesbbb-thiomersal-and-the-blood-brain-barrier-where-does-the-science-stand/)


  1. Conclusions

By now, we should agree that the reason of delaying vaccines in children due to histamine-induced barrier disruption does not stand to science. There is no scientific rationale to support the hypothesis of a massive release of histamine during teething, such release being well below reported values for achieving a BBB disruption and leakage. If you have your baby teething right when he/she is due for immunization, consult with your AAP-accredited pediatrician for what is best for baby.

    5. References

Blakey, G. H., R. P. White, Jr., S. Offenbacher, C. Phillips, E. O. Delano and G. Maynor (1996). “Clinical/biological outcomes of treatment for pericoronitis.” J Oral Maxillofac Surg 54(10): 1150-1160.

Butt, A. M. and H. C. Jones (1992). “Effect of histamine and antagonists on electrical resistance across the blood-brain barrier in rat brain-surface microvessels.” Brain Res 569(1): 100-105.

Cotias, C. T., E. C. de Medeiros, U. V. Lima and C. F. de Santana (1968). “[Determination of histamine release in the blood serum of children during deciduous tooth eruption].” Rev Fac Odontol Pernambuco 1(2): 95-100.

Domer, F. R., S. B. Boertje and S. A. Sweeney (1983). “Blockade of the acetylcholine-and histamine-induced changes in the permeability of the blood-brain barrier of normotensive and spontaneously hypertensive rats by atropine and pyrilamine.” Res Commun Chem Pathol Pharmacol 42(1): 157-160.

Gross, P. M., G. M. Teasdale, W. J. Angerson and A. M. Harper (1981). “H2-Receptors mediate increases in permeability of the blood-brain barrier during arterial histamine infusion.” Brain Res 210(1-2): 396-400.

Laroche, D., P. Gomis, E. Gallimidi, J. M. Malinovsky and P. M. Mertes (2014). “Diagnostic value of histamine and tryptase concentrations in severe anaphylaxis with shock or cardiac arrest during anesthesia.” Anesthesiology 121(2): 272-279.

Mayhan, W. G. (1996). “Role of nitric oxide in histamine-induced increases in permeability of the blood-brain barrier.” Brain Res 743(1-2): 70-76.

Soliman, N. A., S. Abdel Wahed, A. M. Abul Hassan, G. el-Asheiry and A. K. Abdallah (1977). “Systemic disturbances accompanying primary teething: a clinical and pharmacological study.” Egypt Dent J 23(1): 1-8.

Watanabe, M. and W. I. Rosenblum (1987). “In vivo studies of pial vascular permeability to sodium fluorescein: absence of alterations by bradykinin, histamine, serotonin, or arachidonic acid.” Stroke 18(6): 1157-1159.

[Neurosciences/BBB/Stroke] Breaking The Wall: Brain pericytes impairs the BBB integrity following ischemic stroke injury. 

Interesting study, reminds me one of my earlier study. Brain pericytes are a particular cell type with a disputed origin (some think they come from neural crest, some think they come from mesoderm and some think they are mesenchymal stem-cell like cells) that play an important role in the brain and retinal vascular integrity.
Pericytes play an important function by stabilizing vessels and tightening the blood-brain barrier and the blood-retina barrier. Loss of pericytes have been associated with disruption of the retinal barrier in diabetic retinopathy whereas it was associated with leaky vessels and impaired amyloid beta clearance.
Interestingly, pericytes have been also associated with an impaired barrier recovery following stroke injury acceding to this study by Shih and colleagues (http://www.jneurosci.org/…/2016/11/14/JNEUROSCI.2891-16.2016). The mechanism of action is something known as it involves matrix metalloproteinases (MMPs). MMPs are enzymes that cleaves matrix proteins into fragments as well as tight junction proteins. The increase in MMP activity following ischemic stroke injury was known but until now it was mostly associated with astrocytes and endothelial cells. In my previous work, I have demonstrated that pericytes were deleterious to the barrier function following hypoxic stress.

Source: Rogue Cells Leave the BBB Defenseless During Stroke Trending | Labroots | Virtual Events, Webinars and Videos

[Neurosciences] Gutting out the brain: recents studies highlight a contribution of gut microbiota into the pathogenesis of Alzheimer’s and Parkinson’s disease

If there are some neurological diseases that almost everyone know about, it is certainly neurodegenerative diseases such as Alzheimer’s disease (AD), amyotrophic lateral sclerosis (aka Lou Gehrig’s disease), Huntington’s disease (HD) or Parkinson’s disease (PD) for two major reasons: first they are neurodegenerative diseases (that means patients are loosing a particular type of neurons) and incurable (there is no cure to reverse the condition and there is no treatment available to stop the progression). With such diseases, the outcome is grim.
What is interesting with several of these diseases is the formation of protein aggregates or “clumps”. These “clumps” are either due to some mutation in the gene (this is the case of hungtintin and its mutated pathogenic form in HD), formation of protein byproducts (Abeta peptides formed by the cleavage of the amyloid precursor protein by beta-secretase in AD) or yet known exactly known (alpha-synuclein in PD).
In the case of AD, the presence of amyloid plaques (rich in Abeta clumps) and tangles in patients brain was the hallmark pathological feature described by Alois Alzheimer over an 100 years ago. Thus the formation of these Abeta clumps and plaques were seen as the main culprit in the progression of the disease and therefore the main target. A lot of research has been done, clinical trials have been set following promising results in animal models to reduce such plaques formation only to fail miserably in Phase II and III clinical trial (see the recent failure of Lilly’s drug candidate for fighting AD Abeta plaques).
However, some scientists suggested that Abeta plaques were possibly just a consequence of something else preceding. For them the Abeta is considered as a defense to some pathogens, as Abeta peptides have been reported carrying some antimicrobial activity.
In the recent years,  a particular attention has been raised on the gut microbiota and the presence of a “gut-brain axis” involving a possible reciprocal cross-talk between these distant organs.
Two studies published recently brings more information of the contribution of an altered gut-brain axis. One from Frank Sharp (MD) and colleagues from UC-Davis and published recently in Neurology (http://www.neurology.org/content/87/22/2324.full) documented the presence of lipopolysaccharides (LPS), a marker of Gram-negative bacteria and K99 antigen from Escherischia coli (a Gram-negative bacteria commonly found in the mammalian gut and a classical pathogen involved in food poisoning) in brain parenchyma and around vessels. These antigens were also co-localizing Abeta peptide 1-40 and 1-42. We don’t know if this microorganisms can induce Alzheimer’s but it seems that such co-localization suggests some sort of restraining and confinement of the pathogen spreading.
The second one, from Sarkis Mazmanian (PhD) and colleagues from CalTech and published in Cell (http://www.cell.com/cell/abstract/S0092-8674(16)31590-2). Using mice over expressing alpha-synuclein (aSyn), the authors observed that gut microbiota was promoting the onset and progression of aSyn in the brain. This finding is interesting because it matches with another ongoing study presented at the recent annual meeting of the Society of Neurosciences (SfN) that i attended that claimed that aSyn deposition started first in the gut before taking place in the brain. They also found that erasing the gut microbiota was improving the outcome in mice compared to non-treated mice and that treatment of mice with metabolites produced by these bacteria (think about some sort of apple cider juice) resulted in similar effects. In contrast to the first study, this second one show that just metabolites was triggering brain inflammation via microglial cells activation.
It is very interesting to see how the science in these two diseases unfold and for me, it is interesting to see how these metabolites interact with the BBB. Do they passively diffuse? Do they have some transporters? Do aSyn hops from the gut and squeeze into the brain? A lot of questions remains unanswered and again more studies are needed.
Source for the news: www.neurosciencesnews.com

[Pharmacology/Junk Sciences] About the FDA recall on Dr. Hyland’s homeopathic tooth relief….

You may have heard about the recent FDA recall for Dr. Hyland’s homeopathic teeth relief and any products similar to it as listed in their report below (http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm523468.htm).

There are 10 children deaths and 400 adverse events reported with the association of this homeopathic product. Homeopathy has always lauded itself as “natural, effective and harmless”. Even when it was faced with the lack of efficacy, proponents of homeopathy always use the “what’s the harm?” as a defense. Seems that not only it will not treat your ailment. Worse it can kill you. Why? Simple pharmacology.

A tenet of pharmacology is known since Paracelsus with his famous citation “Every substance is poison. No substance is no poison. The dose and only the dose makes a substance a poison”. Even the natural products are poison. You see, Mother Nature in all its grandeur has developed a certain affinity for developing some of the most toxic substances designed to kill living species. Because of evolutionary constraints, plants have been very good as being “chemical plants” and use chemical warfare as a method of invasion and defense.

Now, you can use this poison effect to treat certain conditions. If you find the right dose, you may treat a condition. This is how pharmacology works. Under a certain dose, there is no effect. We only start to see some biological activity after a certain dose. This is what we call the Minimum Efficacy Concentration (MEC). On the other hand, if you reach concentrations high enough, then you start to hit on off-targets and develop the minimum toxic concentration (MTC). This is where we start to see side effects and if the doses are high enough you will see adverse and toxic effects.

Homeopathy is by definition an unproven therapy because its principles defy common laws of physics and chemistry. Because it is relying on extreme dilutions to explain its activity, the amount of active substance is so low that it can be compared to dilute one single molecule into a swimming pool.

In this case, we don’t exactly know what compounds and what amount of each alkaloids are extracted. We know the total amount is 0.0000000000003% or 0.3 pico-grams per 100mL of solution or 100g tablets.


That amount is simply ridiculously low. First, we have to assume that its PO administration will result in a 100% bioavailability (that is probably false and surely below). Second, you should be able to detect the compound in plasma samples. At that level (pg), the odds of detection are very low if not non-different from background. Therefore the odds of having this single molecule finds its target inside a body is almost zero (and the probability is something like 0.0000000000000000000000000000001%).

Yet, homeopathic treatment are all starting from raw extract (usually an hydro-alcoholic solution as extracting solvent) called “tintura matter”. Thats a concentrate and it contains indeed active substances in a high concentration. The nature and quantity of active substance in it are not known and not even reported since homeopathic products are not falling under the FDA supervision (you can thanks the DHSEA provision for that). Basically, no one (even the manufacturer) will tell exactly what and how much of active compounds are inside this tintura matter.

This raises a problem because Mother Nature has been excelling in producing poisons, what only matter is the dose. In the case of the teething relief product, the main culprit appears Atropa belladonna, a common poisonous plant that get easily confused with edible berries.  One of the classical substances purified from Atropa is atropine, an acetylcholine muscarinic receptor blocker. Because Atropa belladonna is known for its poisonous activity, we had some disaster in waiting that was cooking here. Anyone working with drugs will tell you how dangerous it is to overdose on an active substance.

Acetylcholine is an important neurotransmitter in mammalian cells, with peripheral (heart, muscles, lungs….) and central actions. Acetylcholine is a key target of organophosphates and sarin gas, as these agents block its degradation by acetylcholine esterases (this is why you have atropine administered as a side treatment for poisoning).

However, atropine can and will have severe side effects if ingested in a poisoning event (see this case report of accidental ingestion of Belladona: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3361210/)

So whats exactly happened in this situation? We dont know and only now the FDA can provide clues. The FDA is toothless and cannot execute any order unless there are fatality cases involved. On their page, they are aware of the anticholinergic side effects of it but minimized the risk (that logically make sense since the amount is ridiculously low)


At this point, I speculate that something wrong likely happened with these homeopathic products. My speculation is something went wrong with the preparations, resulting in inconsistant extraction and effective concentrations in tintura matter. Because homeopathy are not ruled by FDA, they do not have to follow the stringent quality control and good manufacturing practices (GMP) imposed on pharmaceutical companies. So we have here a production that was on a free ride without any oversight on the QC. Now you can easily imagine that we may have ended up on with overdosed preparations.

Considering the special population (pediatrics), this risk of overdosing was even more amplified. One thing we consider when we develop a drug and prescribe a drug is the benefits/risk ratio. If the risk or adverse effects are too high, the drug cannot be used because it overcomes the benefits.

In that case, not only the benefits were quasi-null, we provided access to a product that was deemed “safe because natural” but indeed has a risk of adverse effect. Now we have likely some precedent in directly demonstrating the danger of poisoning with homeopathic products. This is already the case with essential oils (there are cases of children poisonings with Eos) and now we have the same with homeopathic products.