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'Hi D, hope you and family are doing ok. '
Not too bad thanks CTSFO.
(Off-topic but the physio has told us of a case study, a man with FND. He was in a wheelchair for an extended period before they realised that, on ice, he retained the ability to skate perfectly. He'd learned ice skating as a child and the brain retained the skill more as a reflex. Off the ice again, he still couldn't walk..)
Touk, I’ll be back later and answer both points. I’m not ignoring the post, just a bit busy right now.
ctsfo
you continue to misconstrue what i am saying
i am not talking about kidney damage due to dox i’m talking about potential for kidney damage due to trying to urinate massive amounts of uncleaved ava6000. amounts that might result from very frequent high dosage regime. that is why ava6000 needs to be efficacious in ‘normal’ volumes.
but my main concern is rate of av60000 urination versus rate of cleavage. you cannot say this doesn’t matter because obviously the amount of dox being cleaved in the tme of any particular patient is proportional to strength of ava6000 in the bloodstream at any one time. and if it’s being ****ed away too quickly then that is a big problem. i’d be delighted if you can show me where the data is that shows that. otherwise this is my conclusion from all that’s happened over the last 3 years
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.
Twat of the week won hands down by the sound of it. Eggy has had a break down and so had Derek.
Hi CTSFO,
I've been googling and found this. Do you think that even if Dox (and presumably AVA6000 as AVA6k behaves like dox in the tumour we are lead to believe) could cause kidney damage then another drug along side AVA6k could help prevent that damage?
Highlights
•
Doxorubicin causes significant damage to both the glomeruli and tubules in kidney.
•
Apigenin ameliorates doxorubicin-induced renal injury via inhibition of oxidative stress and inflammation.
•
Apigenin protected renal cells against doxorubicin toxicity without reducing the sensitivity of tumor cells to doxorubicin.
•
Apigenin may serve as a promising protective agent against chemotherapy drug-induced renal toxicity in cancer patients.
https://www.sciencedirect.com/science/article/pii/S0753332221000937#:~:text=tubules%20in%20kidney.-,Apigenin%20ameliorates%20doxorubicin%2Dinduced%20renal%20injury%20via%20inhibition%20of%20oxidative,of%20tumor%20cells%20to%20doxorubicin.
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.
Just remember Touks senior moment when he posted his true identity over social media. Back when he played the village idiot.
Now plays the oncologist Ala eggy. Makes you wonder.
CTSFO may I say a huge thank you for showing touk for what he is. Excellent posts !!!
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.
OK Touk - now say after the rest of us - 'I', 'am', 'rather', 'thick', 'and', 'don't', 'really', 'understand'. Now keep saying that every five minutes for the next couple of years - and you may eventually see in yourself what the rest of us are seeing today!! LoL
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.
CTSFO
I don’t see where it says that kidneys won’t be damaged by having to clear a lot of AVA6000 in a short time.
But we digress. My main thrust is rate of AVA6000 dilution versus rate of cleaving. But hey time will tell when the data is revealed
Touk
The nurses are looking for you,it’s shepherds pie tonight followed by apple crumble back to the home you go…..
“ 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.
as pl75 said, nothing to debate. it's just made up ****e.
It seems to me that the trials to date have shown it works and that it is safe.
The focus now seems to be on how well it works and optimising its use for various situations. Understanding this will take time and the 'answers' won't be instantaneous and likely will be refined with time. Meanwhile it'll be easy meat for the FUDsters to sow their seeds. Keep the faith though.
I weigh those 'facts' against the tumour shrinkage fact that we've been shown, and so what if the half life is short, it's doing it's job.
Could more frequent be better? 3w is based off what we do with dox, which needs a big gap to let the patient recover. If less/no recovery is needed then is 2w better than 3w? We need to know, BP needs to know, the FDA needs to know.
Half life improvement may be beneficial elsewhere.
Again the 2 week test will test both efficacy and toxicity so can the kidneys clear it.
Same facts, different implications.
Same touk.
1. what matters is the amount of dox that ends up in the tumour.
2. the 2w dosing arm was enabled by the safety profile in the 3w. a successful 2w arm enables 2w dosing in the the p2 trial, increases the chances of the trial success.
3. the half life extending serum will have application for different warhead types, and as was stated, the half life of ava6000 is favourable for anthracyclines
4. the kidneys expel crap throughout ones life, it depends on the nature of the crap and whether it damages kidneys or not. no evidence ava6000 is harmful to kidneys.
touk, what a load of trolling crap. even by your low standards this is **** poor stuff from you.
It's very early to be challenging for Twat of the week Touk. Can you please give me some link to verify your factisms.
Don’t you think BP know this stuff?
Ok
1. Low half life was apparent in December slide data and again at AGM - facts
2. P1 trial extended and the arm2 with more frequent dosing - facts
3. New drug IP registered to double half life - fact
4. Kidneys can only handle cleaning so much crap out of the blood - biological fact
Oooh and if you really want a scare - will the modified AVA6000 with double the half life in the blood cleave at a slower rate in the TME - concern
Do you really understand what half life means?
AVCT in for a bag by end of 2024.
POLX in for 3 bags by end of 2024.
DYOR
There’s no debate to be had here, especially with trolls spouting the usual baseless lies for bait. They’ve seen efficacious levels of dox in tumours, they’ve seen reduced side effects. They’re optimising. That’s it. The platform works. Chris has said what she’ll deliver. We wait…
God help anyone who might need Dox as is...surely a company like Avacta, doing all the possibly can to bring their PreCision based product(s) to market ASAP needs our full applause and support. For anyone who has luckily never had to undergo chemotherapy you really and truly have no idea what people have to ensure physically and mentally. Yes, by all means try to understand the science and what it means and where it might lead to investment wise but making out facts are facts when they are clearly not really isn't cricket...
Doxorubicin
Use: Acute lymphoblastic leukemia, acute myeloid leukemia; breast, ovarian, and bladder cancers; Hodgkin lymphoma and non-Hodgkin lymphoma, small-cell lung cancer, gastric cancer, sarcoma, Wilms tumor, neuroblastoma, and thyroid cancer; soft-tissue and bone sarcomas
Dosage: 60–90 mg/m2 single IV injection every 21 days, 20–30 mg/m2/d IV for 3 days every 3–4 weeks, or 20 mg/m2 IV weekly. Total cumulative dose should be 550 mg/m2; reduce dose for liver dysfunction
Toxicities may include: Bone marrow depression, cardiotoxicity, stomatitis (continuous infusion), alopecia, nausea and vomiting, diarrhea, fever, dermatitis at previously irradiated sites, red urine, anaphylactoid reaction
Doxorubicin Pharmacokinetic data
Bioavailability 5% (by mouth)
Protein binding 75%[8]
Metabolism Liver
Elimination half-life Triphasic; 12 minutes, 3.3 hours, 30 hours. Mean: 1–3 hours
Excretion Urine (5–12%), faeces (40–50%)
The most dangerous side effect of doxorubicin is dilated cardiomyopathy, leading to congestive heart failure. The rate of cardiomyopathy is dependent on its cumulative dose, with an incidence about 4% when the dose of doxorubicin is 500–550 mg/m2, 18% when the dose is 551–600 mg/m2 and 36% when the dose exceeds 600 mg/m2. There are several ways in which doxorubicin is believed to cause cardiomyopathy, including oxidative stress, downregulation of genes for contractile proteins, and p53-mediated apoptosis.
Doxorubicin-induced cardiomyopathy typically results in dilated cardiomyopathy, with all four cardiac chambers being enlarged. This results in both systolic and diastolic dysfunction. Eventually, heart failure can result, which carries a 50% mortality rate. There is no effective treatment against established cardiomyopathy caused by the drug as of 2010. The drug dexrazoxane may be used to decrease the risk of doxorubicin's cardiotoxicity in certain cases.
Another common and potentially fatal complication of doxorubicin is typhlitis, an acute life-threatening inflammation of the bowel. Additionally, some people may develop PPE, characterized by skin eruptions on the palms of the hand or soles of the feet, swelling, pain, and erythema. Due to these side effects and its red color, doxorubicin has earned the nickname "red devil" or "red death."
Chemotherapy can cause reactivation of hepatitis B, and doxorubicin-containing regimens are no exception.