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Touk,

Normal circulation: Heart, Arteries, Arterioles, Capillaries, Venules, Veins, Heart.

The heart pushes blood around in this circle. Chemicals leave and enter the blood by crossing the leaky, very thin, walls of the capillaries. This is perpendicular to the flow of blood. It’s dependent on hydrostatic pressure, oncotic pressure, electrostatic forces. Most importantly it’s determined by the size of the molecule and concentration gradient, it is mainly diffusion down a concentration gradient. This process is normally passive in that there isn’t a pump ATP using pump facilitating transfer. Typically the inter capillary distance is 100 micrometers. Very little distance in the extra cellular fluid for molecules to travel. Cells and their blood supply are carefully regulated.

This isn’t the case in cancers. There can be a far larger distance from capillary to cancer cell, so much so some cancer cells are always hypoxic - and these can be more difficult to kill.

Touk, tbf you have raised important questions. I’ll piece the post together. It’s going to read as a bit of a lecture. It is not intended to be patronising, condescending, insulting in any way.

Touk, hope you’re ok. I’ve got some reassuring news about the t1/2 of AVA6000 vs plain doxorubicin. And potentially huge news about the free doxorubicin levels achievable in the TME +/- cancer cells (they’re not necessarily one and the same.) Interested?

GLA

Agree SirJames. Sick of every rise being sold into. Those effing placing shares. They can’t have all been sold forward. And traders know the 19-25p cycle, and keep it going. We have to break out soon.

Thanks Parkez, for this and so many of your other posts. I can remember reading about patents and JV updates ‘in the coming months’ or something similar. Now I can’t find it. But it sounds like the next RNSs should be a bigger wake up call to the market and industry.

Is there a rough guide to when we find out if the patent has been awarded?

Bore Da 🏴󠁧󠁢󠁷󠁬󠁳󠁿 / Good Morning

It’s a small part of the business, but an update on the in-house testing of the heart valve might generate interest. It will give us a guide to the possibilities of the major manufacturers taking an interest.

Touk, that’s correct. Dilution is a function of an increase in the volume of solvent. Providing the circulating volume of blood remains constant, any reduction in drug concentration isn’t being caused by dilution. It’s being caused by drug removal from the circulation. Getting the terms, hence the science, right matters.

What are your thoughts on the variable capillary - cell diffusion distances within the TME, and impact on cellular drug delivery? Asking as a thick Pom Pom waiver! 😇

Touk, it gets more interesting when we discuss the effect of disorganised angiogenesis within the TME and how AVA6000 might therefore be a better means of delivery vs plain doxorubicin.

Touk, re “ The Pom poms picked on kidney damage as an argument they could win and conveniently forgot about AVA6000 half life versus rate of dox cleavage”

This pom pom hasn’t forgotten about t1/2. What we don’t know is what proportion of the exponential decay is caused by renal clearance, and what proportion is determined by uptake into the TME. Though I’ve explained this before, the AVA6000 isn’t getting diluted, it’s getting removed.

Because the concentration of nascent doxorubicin follows this

[nucleus]>[cytoplasm]>[TME] until saturation occurs. We know the uptake into the cell is very rapid. Though the transmembrane transfer is concentration gradient determined, once in the cell the doxorubicin rapidly combines with intra-cellular structures, thus effectively dropping the free doxorubicin concentration, maintaining the gradient, and allowing further drug movement. The RLS will therefore be either delivery of AVA6000 into the TME, or the kinetics of cleavage of nascent doxorubicin from AVA6000 by FAP. By having a high [AVA6000], this promotes the kinetics to allow cleavage.

We know AVA6000 is inert. It can be given by a peripheral cannula in the back of the hand. The patients and healthcare staff don’t know when the drug has been given. The patients don’t feel unwell at the time of administration. Very different to plain doxorubicin - not called the Red Devil out of ignorance.

AVA6000 is obviously man made, but even so, it would need a mechanism by which it causes damage. Being manmade / artificial isn’t enough on its own. And thus far no problems have occurred. I can’t see why Q2W would show up problems when Q3W has shown none. It’s obviously more drug, but an inert drug remains an inert drug.

Touk.. kidney damage or Acute Kidney Injury +/- Chronic Kidney Disease.

The kidney ‘deals’ with toxic and non-toxic chemicals all the time. The majority of the time these chemicals are produced by the human body itself. Urea for example. The body is essentially a huge chemical factory. The kidney doesn’t ‘know’ if a chemical originates from within or without the body. If it can deal with it, it will.

It’s possible for naturally occurring chemicals within the body to damage the kidney. Myoglobin from muscle, glucose if elevated with diabetes, can both irreversibly damage the kidney.

Touk, I’ll be back later and answer both points. I’m not ignoring the post, just a bit busy right now.

Firstly, apologies for getting this wrong in the past.

RUA has a proven ability to protect its IP. To me this makes its present ongoing patent application re heart valve material and manufacture more likely to be accepted and approved quickly.

So my question is, would a major manufacturer choose a JV or simply a takeover? Tesla took over Maxwell in 2019, then sold them in 2021. All they wanted, and all they kept, was the IP to dry electrode technology. Would a major manufacturer consider something similar here? They might not want the manufacturing side, but would rather have everything and then pick and choose what really gives them added value?

GLA

https://pv-magazine-usa.com/2021/07/30/tesla-sells-maxwell-technologies-but-keeps-its-dry-cell-tech-for-lithium-ion-batteries/

Hi D, hope you and family are doing ok. This is an important question. There is plenty of research looking at Co-administration of drugs to reduce the toxic side effect profile of plain doxorubicin. The main area of concern is the myocardial dysfunction. If memory serves me correctly, the cheap as chips drug metformin has been suggested. So the answer is yes to adjunct agents being given with plain doxorubicin.

AVA6000 is a difficult one to answer. If the adjunct drug stops the side effects, do you need AVA6000 at all?

So far, to the best of my knowledge, the side effect profile hasn’t been stopped altogether. Therefore AVA6000 shows a significant improvement in safety thus far. Also AVA6000 targets FAP medium and rich tumours. It only goes where it is needed. So there is an indication for AVA6000 beyond reducing the side effects in liver, kidney, and heart. Only time will tell what the side effect profile of AVA6000 is. It might be beneficial to administer an adjunct agent, but it doesn’t appear to need this at present.

I’m not trying to be nasty or insulting. But we can’t extrapolate or make stuff up. Hepato and nephrotoxicity are specifically looked for in phase 1 studies. Because these are the main routes of metabolism and clearance. They would be mentioned if any evidence of organ dysfunction had occurred.

Touk, phase 1 trials don’t work like that. If renal toxicity had been found it would be mentioned. They don’t mention things that don’t happen. FFS, you could claim AVA6000 could cause any possible side effect because they haven’t specifically been stated not to.

“AVA6000 makes you blind!!!

“WTF???”

“Well they haven’t said it doesn’t.”

It doesn’t work like that. It simply doesn’t. They would have had to have mentioned any evidence of renal toxicity seen thus far.

Touk, sorry to break it to you, doxorubicin is mainly hepatibiliary cleared. Liver, not kidney.

Plasma clearance of doxorubicin is normally in the range of 324–809 ml/min/m2 (Drugs.com 2011) and is mediated by the hepatobiliary pathway. Half of the excreted drug is in the bile, usually being excreted within 5–7 days of treatment, whilst only 5–12% of the drug appears in the patient's urine during the same time period, with 3% of the drug found in urine in the form of doxorubicinol. After 24 h, 10–20% of the drug is excreted in faeces, and 50% after 150 h. In obese women, the rate of systemic clearance is notably decreased. Following a bolus injection of doxorubicin the plasma concentration shows levels of doxorubicinol rapidly increasing and depleting parallel to doxorubicin levels. If the level of drug infusion continues for an extended period of time, the concentration of doxorubicinol will eventually transcend over doxorubicin.[9]

If you can show the data that AVA6000 causes a raise in creatinine, I’d be very interested in seeing it.

“ 4. Kidneys can only handle cleaning so much crap out of the blood - biological fact”

Oh F me, where to start?

The clearance of a drug ie what volume of blood is cleared of a drug in unit time, is an important part of pharmacokinetics. What it DOESN’T mean is a drug is directly nephrotoxic. There are some drugs which are damaging in small overdoses, the majority have to be given in massive overdoses to cause an acute kidney injury. A high plasma level will take longer to drop, and be dependent on what order kinetics are being followed. Ie, is the pathway saturated, thus producing zero order kinetics. But it doesn’t mean it will directly cause AKI. It simply doesn’t.

Touk, FGS, please stop making stuff up. You simply don’t understand pharmacology in sufficient depth. I’m not trying to be insulting or ad hominem in attack, but you’re showing your ignorance to the world.