PRE-CLINICAL TOXICITY STUDIES IN ANIMALS

Contrary to what has been reported in the press, preclinical toxicology studies have been conducted in animals.

You will find below:

- on the one hand, Professor Fourtillan's report on the toxicological studies carried out with the mixed patches of Valentonin (VLT) and 6-Methoxy-Harmalan (6-MH), the results and the conclusion;

- the full reports of the acute toxicity studies for VLT and 6-MH in rats by the oral and transdermal routes. These 4 studies were carried out by CITOXLAB, one of the 2 largest toxicology centres in the world.

 

1 - Report by Prof. Fourtillan concerning the toxicological data from the pharmacological and toxicological studies of the 2 active ingredients of the mixed patches of VLT and 6-MH:

Toxicological studies conducted on the mixed Valentonin (VLT) and 6-Methoxy-Harmalan (6-MH) patches

Professor Jean-Bernard Fourtillan
(Expert Pharmacologist Toxicologist specialized in Pharmacokinetics)

When developing a new drug for human use, its toxicity in animals must first be assessed by conducting preclinical toxicology studies.

This is what I had done during the development of the patches.

In pharmacodynamic (hypnotic activity measurements combined with polysomnographic studies) and pharmacokinetic studies in dogs, we were able to determine the Maximum No Observed Harmful Effect Doses ("DMSEN" in French) by intravenous route.

These no-adverse-effect doses are respectively 3 mg per kg body weight for VLT and, when the 2 pineal hormones are administered simultaneously, 1 mg per kg body weight for 6-MH.

Thus, when a 8 kg Beagle dog is administered simultaneously, 24 mg, or 24000 μg of VLT, and 8 mg, or 8000 μg of 6-MH, as a rapid intravenous drug (bolus IV), no adverse effects are observed.

These doses should be compared to the average doses of VLT and 6-MH, delivered to the body by transdermally, by the mixed patches after 8 hours of application, i.e. 40 μg of VLT and 40 μg of 6-MH.

 

It can be seen that the doses delivered by the patches over 8 hours are 600 times lower for the VLT and 200 times lower for 6-MH than their respective DMSENs in IV bolus.

In view of these toxicological data, we could have dispensed with carrying out an acute toxicity study of VLT and 6-MH by transdermal route.

But in accordance with the rules in force at our manufacturer of the 2 active ingredients (VLT and 6-MH) of the patches, which will synthesize several kilograms of VLT and 6-MH, we had to carry out acute toxicity studies of these 2 hormones by the oral route in rats.


And while we were at it, we had acute dermal toxicity studies of both hormones conducted in rats. This, as we will see below, confirmed the total absence of toxicity of the mixed patches of VLT and 6-MH.

 

Results

Acute toxicity of 6-Methoxy-Harmalan in rats:

- The lethal oral dose value LD50 of 6-Methoxy-Harmalan is 50 to 300 mg / kg body weight in female rats Crl: Wistar. According to GHS criteria, 6-Methoxy-Harmalan can be classified as "category 3" for acute oral exposure.

- The value of the acute median lethal dermal dose LD50 of 6-Methoxy-Harmalan exceeds 2000 mg / kg body weight in male and female rats Crl: Wistar. According to the GHS and GHS-EU (CLP) criteria (4.5), 6-Methoxy-Harmalan can be classified as "Unclassified" for acute dermal exposure.
 

Acute toxicity of Valentonin in rats:

- The lethal oral dose value LD50 of Valentonin is greater than 2,000 mg / kg body weight in female rats Crl: Wistar. According to GHS criteria, Valentonin can be classified in "category 5" (the lowest) for acute oral exposure.

- The value of the acute median lethal dermal dose LD50 of Valentonin was considered to be greater than 2000 mg / kg body weight in male and female rats Crl: Wistar. According to GHS criteria, Valentonin can be classified as "Unclassified" for acute dermal exposure.
 

Conclusion

Valentonin and 6-Methoxy-Harmalan, when administered transdermally, can be considered free of toxicity in humans.

In addition, the mixed patches of VLT and 6-MH will be a drug that has no side effects. This is the consequence of their roles as harmonious regulators of the body (Wake-Sleep system), during the 24 hours of our biological cycle.

 

2 - Extract from the reports of acute toxicity studies conducted by CITOXLAB:

We remind you that CITOXLAB is one of the 2 largest toxicology centres in the world. You can access their website by clicking here.

For reasons of confidentiality, the names and signatures of CITOXLAB employees have been removed.

- "Valentonine: Acute Oral Toxicity Study in Rats" - click here to access the report ;

- "Valentonine: Acute Dermal Toxicity Study in Rats" - click here to access the report ;

 

- "6-methoxy-harmalan: Acute Oral Toxicity Study in Rats" - click here to access the reports ;

- "6-methoxy-harmalan: Acute Dermal Toxicity Study in Rats" - click here to access the report ;