Anti-Neuroinflammatories: Dapansutrile (OLT1177) + Emapunil

mitoMAN

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Dapansutrile (OLT1177)
CAS Number 54863-37-5
https://www.hoelzel-biotech.com/de/...r-dcc-dc20225-100mg-dapansutrile-olt1177.html

and

Emapunil
CAS Number 226954-04-7

https://www.hoelzel-biotech.com/de/medchem-express-inhibitors-other-hy-15527-5mg-emapunil.html

two highly interesting compounds to combat brain inflammation. Both already passed human safety trials.



Dapansutrile:
Dapansutrile proves promising for Alzheimer’s
Dapansutrile prevents inflammatory response, and restores cognitive and behavioral deficits in an Alzheimer’s mouse model

Source:
https://www.drugdiscoverynews.com/d...cu0FsfM5D1XMBpk4bNVcHeLGVMToQl04nc1MHcKAGhhzI

The study shows that oral dosing with dapansutrile inhibits pathophysiological inflammatory processes, recovers significant cognitive losses, and prevents neuroinflammation in the brains of transgenic mice induced with Alzheimer’s. The results point to the therapeutic potential of oral treatment of neuroinflammatory diseases with an NLRP3 inhibitor. Dapansutrile specifically binds to and blocks NLRP3, the sensor molecule integral in the formation of the NLRP3 inflammasome. It has been shown to prevent the formation of the NLRP3 inflammasome, which in turn inhibits the production of interleukin (IL)-1β and IL-18.

Dapansutrile is currently in Phase 2 clinical development; it has been well tolerated and shown to improve clinical outcomes in patients with acute gout flare and heart failure. Olatec also points out that dapansutrile has been observed to have anti-inflammatory properties and other promising activity in a broad spectrum of over 20 preclinical animal models, including arthritis, asthma, acute myocardial infarction, contact dermatitis, multiple sclerosis, melanoma and breast cancers, and spinal cord injury.

Dosings:

"OLT1177™ (Dapansutrile) is a newly developed drug that is safe in humans and inhibits specifically the NLRP3 inflammasome"

Gout Flare study: "Phase 2a trial, adult patients (aged 18-80 years) with a monoarticular monosodium urate crystal-proven gout flare were enrolled at an outpatient clinic in the Netherlands and sequentially assigned using a dose-adaptive design to receive 100 mg/day, 300 mg/day, 1000 mg/day, or 2000 mg/day oral dapansutrile for 8 days"
https://pubmed.ncbi.nlm.nih.gov/33005902/

Heart Failure study: "Subjects were randomized to treatment with dapansutrile for up to 14 days at a ratio of 4:1 into 1 of 3 sequential ascending dose cohorts (500, 1000, or 2000 mg) each including 10 patients. [...] No serious adverse events during the study were recorded."
https://pubmed.ncbi.nlm.nih.gov/33235030/




Emapunil:

Emapunil Holds Promise as Parkinson’s Treatment, Mouse Study...
A compound called emapunil prevented the characteristic loss of nerve cells associated with Parkinson’s disease, lowered levels of dopamine, brain inflammation, and motor deficits in a mouse model of the disease. Researchers suggest that treatment with emapunil, already proven safe in humans
https://parkinsonsnewstoday.com/2019/03/04/emapunil-parkinsons-mouse-study/


The levels of a specific protein, called translocator protein (TSPO), are elevated in microglia during inflammatory activation. TSPO ligands have been used to monitor neuroinflammation, including in patients with Parkinson’s, and have shown neuroprotective effects. However, the mechanisms through which TSPO ligands modulate inflammation are still unclear.

Mice given emapunil also showed normalized expression of genes linked to the innate immune response, production of inflammatory molecules, and nerve cell generation and differentiation, among other processes.
Also, emapunil induced a shift from pro- to anti-inflammatory gene expression in microglia, which may underlie the compound’s protective effects, the team noted.
This compound is able to penetrate into the microglia and flip a molecular switch that attenuates the inflammatory reaction,” Anja Schneider, the study’s senior author, said in a press release. Emapunil, added Schneider, “has already been tested in clinical studies on humans as a possible remedy for anxiety disorders. Therefore, data on this substance exists that proves its safety and tolerability in humans.”
 

Fogbuster

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UPDATE:
about 5 Patients including me will be trialing DAPANSUTRILE in the coming 3-4 months after custom synthesis.
We managed to fund 180 grams of Dapansutrile.
This sounds very interesting. I tried to join your discord link but it says the link has expired. Any chance I can join? Thanks :)
 

mitoMAN

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Some interesting facts about TSPO expression
https://www.nature.com/articles/nrd3295?proof=t


  • TSPO is involved in the translocation of cholesterol from the outer to the inner mitochondrial membrane, which is the rate-limiting step in the synthesis of steroids and neurosteroids and one of the most well-characterized functions of this protein.
  • TSPO expression seems to be a sensitive biomarker of brain damage and neurodegeneration, particularly of inflammation and reactive gliosis.
  • In response to injury, TSPO expression is strongly upregulated in the peripheral nervous system in Schwann cells, macrophages and neurons. Increased TSPO ligand binding has also been investigated as a molecular in vivo sensor of neuronal damage and inflammation in patients with neurodegenerative diseases of the central nervous system (CNS) that are characterized by neuronal loss in discrete areas.
  • Most of the TSPO ligands were developed primarily as neuroimaging agents and diagnostic tools for brain inflammation associated with various neuropathological conditions.

Emapunil:
Emapunil Holds Promise as Parkinson’s Treatment, Mouse Study...
A compound called emapunil prevented the characteristic loss of nerve cells associated with Parkinson’s disease, lowered levels of dopamine, brain inflammation, and motor deficits in a mouse model of the disease. Researchers suggest that treatment with emapunil, already proven safe in humans
https://parkinsonsnewstoday.com/2019/03/04/emapunil-parkinsons-mouse-study/


The levels of a specific protein, called translocator protein (TSPO), are elevated in microglia during inflammatory activation. TSPO ligands have been used to monitor neuroinflammation, including in patients with Parkinson’s, and have shown neuroprotective effects. However, the mechanisms through which TSPO ligands modulate inflammation are still unclear.

Mice given emapunil also showed normalized expression of genes linked to the innate immune response, production of inflammatory molecules, and nerve cell generation and differentiation, among other processes.
Also, emapunil induced a shift from pro- to anti-inflammatory gene expression in microglia, which may underlie the compound’s protective effects, the team noted.
This compound is able to penetrate into the microglia and flip a molecular switch that attenuates the inflammatory reaction,” Anja Schneider, the study’s senior author, said in a press release. Emapunil, added Schneider, “has already been tested in clinical studies on humans as a possible remedy for anxiety disorders. Therefore, data on this substance exists that proves its safety and tolerability in humans.”



Unlike undesirable effects associated with conventional
benzodiazepines, AC-5216 (Emapunil) had no myorelaxant effects, did not
affect the memory (passive avoidance response) or prolong
hexobarbitone-induced sleep in mice, even at doses as high as
1000 mg/kg
, p.o., although it did slightly prolong the ethanolinduced sleep time at 1000 mg/kg.

LOW TOLERANCE?
AC-5216 when repeatedly administered for two weeks does not
induce tolerance to its anxiolytic-like effects or emotional and
somatic withdrawal symptoms.
In contrast, diazepam treatment
withdrawal not only induced anxiogenic-like effects on the second
day of the withdrawal period, but also decreased body weight
gain and brought about body weight loss in mice.

STRONG TSPO BINDING!
XBD173 exerted acute anxiolytic effects, which were prevented by the TSPO antagonist PK11195, in the social exploration test and the elevated plus maze test in rats.

IMMEDIATE EFFECT
These preclinical studies suggest that XBD173 exerts rapid anxiolytic and antipanic effects with a more favourable side-effect profile than that of benzodiazepines


Pharmacology:
At the cellular level, the selective TSPO ligand XBD173 potentiated the amplitude and duration of GABA-mediated inhibitory postsynaptic currents in mouse medial prefrontal cortical neurons, which was prevented by finasteride. In contrast to diazepam, XBD173 did not act directly on postsynaptic GABAA receptors expressed in human WSS1 cells expressing rat α1γ2 and human β3 GABAA receptor subunits. These data provide further evidence that neurosteroidogenesis is involved in the differential effects of TSPO ligands on GABAergic neurotransmission. Neurosteroids modulate GABAA receptors via an allosteric site different from that targeted by benzodiazepines. These distinct sites of action at the GABAA receptor might explain the lack of tolerance development and withdrawal symptoms after XBD173-induced neurosteroidogenesis
 
Last edited:

mitoMAN

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UPDATE:
Panic Disorder
To investigate the anxiolytic potential, The TSPO agonist, XBD173 (Emapunil), has been investigated in healthy male volunteers using the cholecystokinin tetrapeptide (CCK4) challenge – a human model of panic- like anxiety. CCK4 fulfills the criteria for an ideal panicogenic agent and the panic induction by CCK4 is sensitive to clinically effective anxiolytic agents, including benzodiazepines.
Out of 85 subjects, 71 healthy volunteers that showed a clear panic response to the neuropeptide CCK4 were randomized into one of five treatment arms (n=14 in each group) which consisted of 7 days treatment with either placebo, the benzodiazepine alprazolam (2 mg/day), or one of three doses of XBD173 (10, 30, or 90 mg/day). A second CCK4 challenge was performed following the dosing
period. At the highest dose (90 mg/day), XBD173 attenuated CCK4-induced anxiety compared to placebo (p<0.036) to a degree similar in magnitude to the benzodiazepine.
The number of side effects reported with XBD173 was comparable to the incidence in the placebo group. In contrast, a much higher incidence was reported by the alprazolam treated group, in particular dizziness and somnolence. While 57% of the subjects treated with alprazolam complained of withdrawal symptoms such as sleep disturbances or restlessness, these were almost absent in the XBD173 treated groups.



At the highest dose (90 mg/day), XBD173 (Emapunil) attenuated CCK4-induced anxiety compared to placebo (p<0.036) to a degree similar in magnitude to the benzodiazepine alprazolam 2mg/day.
While 57% of the subjects treated with alprazolam complained of withdrawal symptoms such as sleep disturbances or restlessness, these were almost absent in the XBD173 treated groups. The number of side effects reported with XBD173 was comparable to the incidence in the placebo group.

So if we already benefit from lets say 0.5mg per day of alprazolam - then maybe 25mg Emapunil would be enough already. For me personally 0.5mg Lorazepam is a good dosage - havnt compared it to alprazolam tho.

-> This would mean. 1 gram costs 900USD and would last 40 days.
If we buy 10 gram that would be 490USD for 40 days.


SOURCE:
https://www.ecnp.eu/~/media/Files/ecnp/Projects and initiatives/Medicines Chest/XBD173.pdf
 

mitoMAN

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Update: Dapansutrile tested for COVID related Cytokine Storm
https://clinicaltrials.gov/ct2/show/NCT04540120
Safety and Efficacy of Dapansutrile for Treatment of Moderate COVID-19 Symptoms and Evidence of Early Cytokine Release Syndrome

Experimental: dapansutrile capsules
Subjects will receive 4 x 250mg dapansutrile capsules BID for 14 days with an initial (first) dose of 8 x 250mg (2000 mg) administered at the study site on Day 1 (Day 1 dose may be 3000 mg).

Article:
https://www.businesswire.com/news/h...s-Selective-NLRP3-Inhibitor-Oral-Dapansutrile
 

mitoMAN

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Evidence for neuro-inflammation in MECFS?
I dont think neuroinflammation is a huge problem for mild-moderate patients. But defintely for severe - very severe patients.
Depending on selection of patients, the study will either be positive or negative.

1.
https://pubmed.ncbi.nlm.nih.gov/24665088/
Neuroinflammation in Patients with Chronic Fatigue Syndrome/Myalgic Encephalomyelitis: An ¹¹C-(R)-PK11195 PET Study

@Pyrrhus made a good comparison of both studies posted by you and this one.

2.
https://pubmed.ncbi.nlm.nih.gov/29348371/
[Neuroinflammation in the Brain of Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome]
Neuroinflammation
was found to be widespread in the brain areas of the patients with ME/CFS and was associated with the severity of their neuropsychological symptoms


Article about it by Healthrising
https://www.healthrising.org/blog/2...mation-found-chronic-fatigue-syndrome-me-cfs/

3. Article by OMF -
MEA Summary Review: Study suggests brain inflammation in ME/CFS | 15 January 2019
https://www.omf.ngo/wp-content/uplo...unger-How-Brain-Inflammation-Causes-MECFS.pdf
Jarred Younger, PhD | How Brain Inflammation Causes ME/CFS

Article about it:
https://meassociation.org.uk/2019/0...brain-inflammation-in-me-cfs-15-january-2019/
Study:
https://link.springer.com/article/10.1007/s11682-018-0029-4

Good Video of Dr. Younger explaining:


4. First Mouse Model of Chronic Fatigue Syndrome
https://www.jstage.jst.go.jp/article/bpb/43/1/43_b19-00616/_html/-char/en
Neuroinflammation, Oxidative Stress, and Neurogenesis in a Mouse Model of Chronic Fatigue Syndrome, and the Treatment with Kampo Medicine


5. A neuro-inflammatory model to explain the onset, symptoms, and flare-ups of ME/CFS
https://ccisupport.org.nz/research/a-neuro-inflammatory-model/



A view Summaries:

https://me-pedia.org/wiki/Neuroinflammation