Parkinson's Disease Drug Lethality most likely related to Endotoxin Gut Dysbiosis

Entacapone and Loxapine Succinate alter the Gut Microbiome favouring E. coli with increased toxicity. Iron Chelation by these and other drugs causes Death and Injury.

Thanks to my friend Gary Sharpe¹ for letting me know about a recent free download study² showing two drugs, Entacapone and Loxapine Succinate, used in attempted treatment of Parkinson’s Disease, alter the Gut Microbiome by inducing Iron deficiency. See also the back story behind this project.³

The paper by Fátima C. Pereira and coworkers is very interesting because it used the Deuterium isotope of Hydrogen and advanced spectrocopic and imaging techniques to track alteration of the microbiome. Here is part of their Figure 6.

d, Schematic representation of the working hypothesis. In the absence of entacapone (left), enough iron is available to most gut microbiome members. Under ENT-Hi conditions, entacapone complexes available iron (ENT:Fe), and only organisms able to produce and/or import siderophores (represented by diamonds) for iron scavenging are able to grow and thrive (right).

e, Increase in the AMR and virulence index in no drug controls and entacapone (ENT-Hi)-treated samples. Boxes represent the median, first and third quartiles. Whiskers extend to the highest and lowest values that are within 1.5× the interquartile range.

Indicated P values were obtained from unpaired two-sided t-test comparing the groups ‘Ent-Hi’ and ‘No drug’ at each indicated timepoint.

Note there is a paywalled paper published just 1 day after on the same effect with Entacapone.⁴ We can see their graphical abstract which is rather fuzzy but does indicate they were interested in Iron Scavenging Bacteria that produce Siderophores, a fancy name for molecules that chelate Iron, such as EDTA.⁵

Entacapone Deaths at FAERS

Prompted by Gary, I had a quick look at Wikipedia entry for Entacapone, a known chelator of Ferric Iron.⁶

Then I looked at US FAERS to see how many people were killed and injured Entacapone to 30 September 2024.

268 Deaths, 2448 serious 2,708 total cases

Loxapine Deaths at FAERS

Nasty looking molecule but not a chelator of Iron.

In your body the methyl group on the top right hand Nitrogen atom is removed.⁷

To 30 September 2024

Loxapine 652 Deaths, 3,736 serious 3,784 total cases

Loxapine Hydrochloride 16 Deaths, 60 serious 65 total cases

Loxapine Succinate 252 Deaths, 1,373 serious 1,646 total cases

Note that Succinate⁸ is an Iron chelator and the solubility of Iron Succinate will be lower in the Gut than in the acid Stomach.

Ferric Succinate was found to essentially insoluble⁹ above pH 4.65.

Note that FAERS data for Loxapine would be subject to inaccuracy because those reporting would not always see the Succinate derivative as relevant.

Death and Injury Mechanisms

Apart from the pharmacology and lack of efficacy of the drugs, the recent papers serve to confirm the known effects of Leaky Gut leading to Parkinson’s Disease via Endotoxin.¹⁰¹¹

See also use of Deuterium in studies of Endotoxin poisoning at Robert Koch Institute.¹²

DMSO leads to increased Iron Chelation

An interesting experiment by Fátima C. Pereira and coworkers showed that Dimethyl Sulfoxide (DMSO), in pre-complexation reactions, when Fe(II) from FeSO4 was exposed to the drug solvent, resulted in an instantaneous oxidation to Ferric Iron [Fe(III)] (Extended Data Fig. 9b).

Here is part of their Extended Data Figure 9b.

b. Absorbance at 562 nm, indicating the presence of ferrozine-Fe(II) complexes in solutions of FeSO₄ in degassed DMSO (100%) or degassed double distilled water, following reaction with increasing concentrations of ferrozine

Ferrozine (also known as PDTS) or 3‐(2 pyridyl)‐5,6‐bis (4‐phenyl‐sulfonic acid)‐l,2,4‐triazine, can quantitatively form complexes with Ferrous iron yielding a red colour but interacts weakly with Ferric Iron.¹³

The devastating effect of DMSO causing spontaneous oxidation to Iron III using Ferric Chloride as control is also evident to the naked eye in the top left of their Figure 4.

It is interesting that the toxic form of Iron found in the blood of patients suffering from many haemoglobinopathies and haemochromatosis has recently been identified as a mixture of Iron(III) Citrate complexes.¹⁴

1. https://substack.com/@garysharpe

2. Fátima C. Pereira, Xiaowei Ge, Jannie M. Kristensen, Rasmus H. Kirkegaard, Klara Maritsch, Dávid Szamosvári, Stefanie Imminger, David Seki, Juwairiyah B. Shazzad, Yifan Zhu, Marie Decorte, Bela Hausmann, David Berry, Kenneth Wasmund, Arno Schintlmeister, Thomas Böttcher, Ji-Xin Cheng and Michael Wagner. 21 November 2024. The Parkinson’s disease drug entacapone disrupts gut microbiome homoeostasis via iron sequestration. https://www.nature.com/articles/s41564-024-01853-0

3. https://communities.springernature.com/posts/off-target-effects-of-a-parkinson-s-disease-medication-on-the-gut-microbiome

4. Jan Homolak, Lara Berg and Lisa Maier. 22 November 2024. Parkinson’s drug starves gut microbes of iron. https://www.nature.com/articles/s41564-024-01863-y

5.

6. https://en.wikipedia.org/wiki/Entacapone

7. https://en.wikipedia.org/wiki/Loxapine

8. https://en.wikipedia.org/wiki/Succinic_acid

9. TAKESHI SUZUKI, FERGUS M. CLYDESDALE, and TIRA PANDOLF. 1992. Solubility of Iron in Model Systems Containing Organic Acids and Lignin. Journal of Food Protection. 55(11):893-898

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13. EE Pierson and RB Clark. 1984. Chelating agent differences in ferrous iron determinations. https://www.tandfonline.com/doi/abs/10.1080/01904168409363177

14. Robert C. Hider, André M. N. Silva and Agostino Cilibrizzi. 2024. The iron(III) coordinating properties of citrate and α‑hydroxycarboxylate containing siderophores. Biometals 21 May 2024. https://doi.org/10.1007/s10534-024-00607-z