Monepantel: a brain-penetrant mTOR inhibitor

#26

@adssx meclizine crossed the BBB. What’s wrong with using that instead? Dramamine

#27

“Meclizine extends male mouse lifespan by ~8%.
Astaxanthin prolongs the lifespan of male mice by ~12%.
Interestingly, fisetin, a compound known for eliminating aging-related dysfunctional cells (senescent cells), confers no effects on either mouse lifespan or tissue senescence.”

The effect on mTORC1 is mild even at relatively high doses.

In addition, meclizine inhibits mitochondrial respiration, which is not a good thing.

Meclizine is also an anticholinergic, which is also not a good thing, especially for the elderly. But maybe this could be mitigated by a choline supplement.

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#28

Didn’t know re: anticholinergic bit. Makes sense.

#29

I don’t think there’s data on this.

Meclizine => anticholinergic => bad?

#30

“Meclizine is a first-generation antihistamine.”
"Meclizine is an anticholinergic.

“First-generation antihistamines also tend to have notable anticholinergic properties (blocking acetylcholine receptors)”

I was wrong in suggesting that choline supplements might mitigate the effects of anticholinergic medications because the medications block the receptors and do not diminish the amount of choline in your system.

“According to the American Geriatrics Society (AGS Beers Criteria 2023), the long-term use of anticholinergic medications such as meclizine is associated with an elevated risk of delirium, falls, delirium, and dementia among older adults.”

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#31

That’s why the quest for a safe BBB-crossing mTOR inhibitor is still on. Hopefully, monepantel will be the one.

@CronosTempi after discussing with Ora Biomedical, a C. Elegans test is probably useless as monepantel is a dewormer even at low dose, but we might try on C. Elegans with the target gene acr-23, knocked out. Alternatively, we might try on zebrafish and Drosophila? I can ask WuXi for a quote. But which doses should we test?

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#32

Well, fish and flies are too far from mammals, so there probably is no sense in trying to extrapolate dosing in humans per body weight to these little creatures. The usual procedure in labs is to do a series of doses to see which one gives effects. Probably not practical in this scenario, so it’s just going to be a guessing game. Maybe the dose can be derived from gene targets:

Phylogenomics of Ligand-Gated Ion Channels Predicts Monepantel Effect

“The nematode species in the Caenorhabditis genus, equipped with ACR-23/MPTL-1-like receptor subunits, are sensitive to monepantel (EC50<1.25 µM), whereas the related nematodes Pristionchus pacificus and Strongyloides ratti , which lack an ACR-23/MPTL-1 homolog, are insensitive (EC50>43 µM). Genome sequence information has long been used to identify putative targets for therapeutic intervention. We show how comparative genomics can be applied to predict drug sensitivity when molecular targets of a compound are known or suspected.”

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#33

Yes we need to do a dose response but I just don’t know which 3 doses to start from. Then we can ask a Chinese lab such as WuXi to run the study.

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#34

I no longer have a farm and hence no sheep or goats. That makes buying zolvix in the UK difficult. Does anyone know of a company that exports it to the UK.

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#35

It seems that you can order online but I don’t know how much information they require: Elanco Zolvix 25mg/ml Oral Solution - Farmacy

There are Canadian, Australian, South African and Argentine websites but I don’t know if they ship abroad:

In France or Belgium you need a prescription and they don’t deliver abroad: Zolvix 25mg/ml Sol Orale Pour Moutons 500ml - Pharmacie Stassen-Bya

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#36

In the Uk I need to give details of the flock

#37

South Africans and Argentinians might be more open to ship without that… Zolvix doesn’t seem to be approved in India or Turkey.

#38

My late ex wife had a few goats, but that was some years ago.

#39

In ALS: NUZ-001 OLE Study Demonstrates Long-Term Safety and Efficacy Signals

NUZ-001 significantly increased survival (χ2=13.75, p=0.00021)
NUZ-001 significantly reduced the risk of death by 76.7% (HR=0.233, p=0.0013)
Treatment with NUZ-001 showed an estimated median survival extension of ~16 months
NUZ-001 slowed the rate of functional decline by 31% (–0.83 vs –1.21 ALSFRS-R points/month; p = 0.145)
NUZ-001 reduced the rate of respiratory decline by 43% (–1.65 vs -2.93 VC PP points/month; p=0.078)
NUZ-001 has been safely used for more than 2.5 years, with five patients still receiving treatment under the TGA’s Special Access Scheme

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The OLE study was an open-label, safety, tolerability, and preliminary efficacy study of NUZ-001 in 10 patients with ALS who completed the Phase 1 MEND Study, at the recommended Phase 2 dose of 10 mg/kg administered orally daily for 12-months.

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#40

In terms of safety @John_Hemming, phase 1 in cancer found gastrointestinal adverse events at 25 mg/kg (ref.: ACTRN12614000612617).

#41

FDA Lifts Clinical Hold on NUZ-001

  • U.S. FDA lifts the Clinical Hold on NUZ‑001, Neurizon®’s lead investigational therapy for ALS
  • Clears the way for entry into the HEALEY ALS Platform Trial expected to commence in Q4 CY2025
  • IND supported by robust preclinical safety data and comprehensive manufacturing and quality information from the previously signed Elanco licensing agreement
  • Expedites NUZ-001 as a platform molecule with pipeline expansion potential for other neurodegenerative diseases
  • Positions Neurizon for accelerated regulatory pathways and future partnering opportunities
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#42

FDA Clears NUZ-001 for Entry into HEALEY ALS Platform Trial

Highlights:

  • FDA has completed their review of the Neurizon NUZ-001 regimen to the HEALEY ALS Platform Trial Master Protocol
  • This marks the official entry of NUZ-001 as Regimen I in the HEALEY ALS Platform Trial
  • Next steps include obtaining single IRB approval, site initiations and clinical start-up activities ahead of commencement of patient enrollment expected early in 2026
  • Milestone strengthens Neurizon’s pathway toward advancing a potential new treatment for ALS
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#43

NUZ-001 Data Shows Multi-Pathway Protein Clearance

New preclinical data show NUZ-001 increases activity of multiple protein clearance pathways in neuronal models
Demonstrates enhanced activity of both autophagy and proteasomal systems, key processes involved in clearing aggregated proteins
Supports a differentiated, multi-pathway approach targeting disrupted protein homeostasis in
neurodegenerative disease
Findings further characterise the biological activity of NUZ-001 and strengthen its scientific foundation
Continues to build evidence supporting NUZ-001 as it progresses through clinical evaluation

If anyone here knows how to purchase and deliver monepantel… Asking for a friend :eyes:

#44

Procurement Market Analysis: Standardized Monepantel (Zolvix)

In the context of biotech and healthcare longevity research, identifying and sourcing compounds that influence metabolic pathways requires navigating fragmented international supply chains. Procuring standardized Monepantel presents an immediate logistical hurdle: the compound is not commercially manufactured in tablet or capsule form.

Acquiring Monepantel at scale practically dictates sourcing veterinary oral drenches (Zolvix and Zolvix Plus) from agricultural suppliers in Australia, New Zealand, and the UK. Currently, Monepantel lacks FDA approval for domestic veterinary use in the US, making direct local procurement impossible outside of highly priced research chemical suppliers.

A critical analytical constraint: The widely available “Zolvix Plus” formulations contain Abamectin (2 mg/mL) alongside Monepantel (25 mg/mL). If your objective is isolated molecular investigation, the presence of a macrocyclic lactone like Abamectin introduces significant confounding variables and an altered toxicity profile. Pure research-grade Monepantel powder is included at Rank 10 to illustrate the extreme cost disparity of isolating the compound without parasiticides.

All veterinary liquid formulations below contain a standardized concentration of 25 mg/mL of Monepantel. Foreign currencies (AUD, GBP, NZD) have been converted to approximate USD values for direct comparison.

Rank Product/Brand Name (Exact title) Vendor Total Weight (Original Unit & Grams) Total Price (USD) Cost Per 250mg of Monepantel 3 (Zolvix) Number Capsules or tablets Needed
1 Zolvix Plus Low Voloume Oral Anthelmintic Broad Spectrum Drench for Sheep 10 Lt The Farmers Mailbox (via eBay) 10 Liters (approx. 10,000g) $1,938.45 **$1.94**
(Calculation: 1938.45 / 250000 * 250) 		0 (Commercial capsules do not exist. Requires 10 mL liquid dose.)
2 Elanco Zolvix PLUS - Combination Sheep Drench (10L) Aussie Vet Products 10 Liters (approx. 10,000g) $2,035.12 **$2.04**
(Calculation: 2035.12 / 250000 * 250) 		0 (Commercial capsules do not exist. Requires 10 mL liquid dose.)
3 Zolvix Sheep Drench Oral Solution - POM (1L) StowAg 1 Liter (approx. 1,000g) $204.12 **$2.04**
(Calculation: 204.12 / 25000 * 250) 		0 (Commercial capsules do not exist. Requires 10 mL liquid dose.)
4 Elanco Zolvix PLUS - Combination Sheep Drench (5L) Aussie Vet Products 5 Liters (approx. 5,000g) $1,086.77 **$2.17**
(Calculation: 1086.77 / 125000 * 250) 		0 (Commercial capsules do not exist. Requires 10 mL liquid dose.)
5 Zolvix Plus for Sheep and Cattle (1L) Specialist Sales 1 Liter (approx. 1,000g) $230.75 **$2.31**
(Calculation: 230.75 / 25000 * 250) 		0 (Commercial capsules do not exist. Requires 10 mL liquid dose.)
6 Zolvix Plus Sheep & Cattle Oral Drench 1L The Farmers Mailbox 1 Liter (approx. 1,000g) $232.58 **$2.33**
(Calculation: 232.58 / 25000 * 250) 		0 (Commercial capsules do not exist. Requires 10 mL liquid dose.)
7 Zolvix Plus Broad Spectrum Oral (1L) N & W Livestock 1 Liter (approx. 1,000g) $234.00 **$2.34**
(Calculation: 234.00 / 25000 * 250) 		0 (Commercial capsules do not exist. Requires 10 mL liquid dose.)
8 Elanco Zolvix PLUS - Combination Sheep Drench (1L) Aussie Vet Products 1 Liter (approx. 1,000g) $259.97 **$2.60**
(Calculation: 259.97 / 25000 * 250) 		0 (Commercial capsules do not exist. Requires 10 mL liquid dose.)
9 Zolvix Plus Oral Drench for Sheep and Cattle (1L) PGG Wrightson 1 Liter (approx. 1,000g) $311.40 **$3.11**
(Calculation: 311.40 / 25000 * 250) 		0 (Commercial capsules do not exist. Requires 10 mL liquid dose.)
10 Monepantel TargetMol 100 mg (0.1g) $1,530.00 **$3,825.00**
(Calculation: 1530.00 / 100 * 250) 		0 (Raw powder. Requires exact weight measurement; no commercial capsule exists.)

Shipping & Procurement Logistics

  • Customs & Importation: Because Zolvix is an unapproved veterinary drug in the USA, importing it from foreign agricultural suppliers carries an inherent risk of seizure by US Customs and Border Protection (CBP) or the FDA.
  • Freight Surcharges: International shipping is not included in the base prices above and must be scheduled via third-party freight forwarders or international courier programs (e.g., DHL).
    • Australia/NZ to USA: Expect flat-rate international freight fees ranging from $50.00 to $120.00 USD, heavily dependent on the total liquid weight. Heavy drums (like the 10L option) incur substantial dimensional weight surcharges.
    • UK to USA: Requires specific agricultural export clearance for POM-VPS (Prescription Only Medicines - Veterinarian, Pharmacist, Suitably Qualified Person) tier medications.
    • eBay Global Shipping: Rank 1 leverages eBay’s global network, offering the highest probability of streamlined customs clearance, with shipping rates calculated dynamically at checkout based on zip code.
    • TargetMol: Source 10 ships domestically from USA stock. Shipping is standard hazardous chemical freight, typically $35.00 to $50.00 depending on cold-chain requirements.
#45

Thanks. That’s a problem. Abamectin is an anthelmintic like ivermectin. We need pure Monepantel (Zolvix). Courtesy of ChatGPT:

It’s also approved in Australia and NZ, but it seems only Zolvix Plus is approved there.

ChatGPT: “HPRA says that from 1 December 2025, all antiparasitic veterinary medicinal products for use in food-producing animals in Ireland are subject to veterinary prescription (POM).”

So if someone has a farm and is willing to reexport…