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175 replies to this topic

#91 pone11
Posted 06 February 2015 - 09:30 PM mag1, on 06 Feb 2015 - 10:17 PM, said: By the way does anyone know the answer to the million dollar question: What is the industrial use of 3-Bromopyruvate?
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When you go online, there are Chinese wholesalers that will accept orders for 3-BP at a minimum order size of 25 kg. Some of these suppliers note that they could supply 1000 tons per month of it. What possible industrial use is there for so much 3-BP? Curing the patient in Germany took 128mg doses! The huge industrial application of 3-BP (more than anything else) clarifies the difficulty anticipated in patenting it.

The answer is not easily found online (if it is even present).

[Hint: The answer, if correct makes total sense.]

Anyone?

(Accept rain checks?) 3BP may be a pseudo-pyruvic acid substitute, or would be used in similar situations. Pyruvic acid is a starting material for pharmaceuticals like L-tryptophan, L-tyrosine and alanine, as well as L-DOPA. It is used industrially in crop protection products, polymers, cosmetics, and food additives. This article is about generic pyruvic acid applications:http://link.springer...7/s002530100804 I absolutely love that 3BP is being mass produced for many applications, and the Chinese are heavily involved in that. Nothing the FDA can say or do will stop its production at this point. Thank God for miracles. Edited by pone11, 06 February 2015 - 09:39 PM.


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#92 mag1
Posted 06 February 2015 - 09:39 PM Not bad. That is pretty close.
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$1250 per ton to make pyruvate. It would be interesting to know the production process used to make 3-Bromopyruvate. The impurities would then be known.

From what I understand, it is used as a fungicide which completely makes sense. Shutting off cellular respiration would do it.
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#93 mag1
Posted 06 February 2015 - 09:51 PM Therein lies the problem: without a patentable product 3-BP could just sit there.
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No one might bother developing it. Without some profit motive it could go nowhere. The company developing it has decided to wait over 2 years after the FDA gave immediate clearance to start a phase 1 trial. That could cost a lot of money as the patent clock is ticking. The company recently stated that the trial might be further delayed until this spring.

There would be too many lingering questions about safety and effectiveness without proper clinical trials for it to become a widely accepted treatment. There is so much uncertainty now surrounding 3-BP as a treatment. 3-BP needs some sort of profit driver to move forward. Knowing that Chinese suppliers could supply thousands of tons of high grade product at minimal cost would be a problem.

And of course 3-BP could displace the many high priced cancer pharmaceuticals, many of which have never shown impressive effectiveness.
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#94 mag1
Posted 06 February 2015 - 10:09 PM The quote from the patent was noting toxicity at certain dosing ranges. It is important to read the patent further to understand the context when used in the dose range of the German patient. The patent was filed from the Johns Hopkins group. The Johns Hopkins group was also involved in the care of the German patient, so the information on toxicity from the patent would have been known to them.
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It should be noted that the German patient article stated:

"Regeneration of liver tissue was also observed and the data are being analyzed for future publication."

and,

"Despite regeneration of the healthy liver cells, this process apparently could not compensate adequately for the rapid destruction of tumor cells and could not detoxify the dead cancer cell debris fast

enough."

and,

"A patented and proprietary formulation of 3BP is safe at the concentrations (2–3.5 mg/kg body weight) employed for TACE delivery in humans. No major cyto-toxicities of this specially formulated 3BP have been observed. Please note that unformulated 3BP may be harmful in some cases."

and,

"Liver regeneration is not inhibited by 3BP treatment."

The article is claiming 3-BP was not directly toxic to the liver.

An autopsy would have provided confirming evidence.

Edited by mag1, 06 February 2015 - 10:10 PM.


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#95 pone11
Posted 06 February 2015 - 10:15 PM mag1, on 06 Feb 2015 - 10:51 PM, said: Therein lies the problem: without a patentable product 3-BP could just sit there.
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No one might bother developing it. Without some profit motive it could go nowhere. The company developing it has decided to wait over 2 years after the FDA gave immediate clearance to start a phase 1 trial. That could cost a lot of money as the patent clock is ticking. The company recently stated that the trial might be further delayed until this spring.

There would be too many lingering questions about safety and effectiveness without proper clinical trials for it to become a widely accepted treatment. There is so much uncertainty now surrounding 3-BP as a treatment. 3-BP needs some sort of profit driver to move forward. Knowing that Chinese suppliers could supply thousands of tons of high grade product at minimal cost would be a problem.

And of course 3-BP could displace the many high priced cancer pharmaceuticals, many of which have never shown impressive effectiveness. If it is really a cure, the cat is out of the bag and it cannot be stopped. The way drug companies kill something like this is getting the FDA to shut down production. They can't do it, and FDA cannot touch people outside the US from experimenting, treating, and publishing research.

I suspect this is how 3BP will work out in the US:   Cancer doctors will be trained by their masters in the drug industry to use 3BP as an adjunct to their toxic drugs. The pharmaceuticals will claim it is their poison that kills the cancer even though it was 95% just 3BP. They will all struggle to manufacturer "studies" that show that 3BP +  is 5% more effective than 3BP alone, and then use that fact to justify charging $100K more for the therapy. Groups will also develop "proprietary" versions of 3BP, which is fine if they add value.

There is a chance that one or more groups - in or out of the US - will develop therapies using 3BP alone that are effective for early stage cancers and charge for that therapy at extremely low prices. Given the climate of greed, corruption, government mismanagement of costs, etc, I doubt it will happen. But it could happen and I will say a prayer for it.

Edited by pone11, 06 February 2015 - 10:31 PM.


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#96 pone11
Posted 06 February 2015 - 10:29 PM mag1, on 06 Feb 2015 - 11:09 PM, said: It should be noted that the German patient article stated:
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"Regeneration of liver tissue was also observed and the data are being analyzed for future publication."

The fact that liver regenerates after 3BP treatment says nothing about whether "normal" liver cells might have been destroyed during 3BP treatment. They are playing with words.

mag1, on 06 Feb 2015 - 11:09 PM, said: "Despite regeneration of the healthy liver cells, this process apparently could not compensate adequately for the rapid destruction of tumor cells and could not detoxify the dead cancer cell debris fast

enough."

and,

"A patented and proprietary formulation of 3BP is safe at the concentrations (2–3.5 mg/kg body weight) employed for TACE delivery in humans. No major cyto-toxicities of this specially formulated 3BP have been observed. Please note that unformulated 3BP may be harmful in some cases."

"Liver regeneration is not inhibited by 3BP treatment."

The article is claiming 3-BP was not directly toxic to the liver.

An autopsy would have provided confirming evidence. They make a claim that "apparently" the process could not compensate for destruction of the tumor cells. Where is the proof of this claim?

I am skeptical because page 169 of the German liver report says they are "surprised" by the ascites that started showing up in late 2009:

http://link.springer...0863-012-9417-4

Since they didn't understand that result, or autopsy after death, this leaves open the possibility that the 3BP treatments did in fact destroy some healthy liver cells unexpectedly, just as they did in the animal studies you linked in rabbits and rodents. And I trust those animal studies, which provided very thorough and compelling autopsies of the animals more than I do a hearsay n=1 human study where there was no autopsy.

Why are there no human studies on early stage cancers of different types? It's unbelievable that these have not been published.

Edited by pone11, 06 February 2015 - 10:34 PM.


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#97 niner
Posted 06 February 2015 - 10:46 PM Yeah, I think the toxicity of 3BP is non-trivial. Things like this are usually more toxic and less effective than they first appear, once they get into serious well-run trials with a lot of patients. As to the financial aspects of this, the Chinese product that's made in ton quantity is not a pharmaceutical grade. It's probably closer to what chemists call a "technical" grade, or maybe worse. If you want to go into humans, you need to develop a manufacturing method that is extremely clean. You can get a patent on the manufacturing method, if not the molecular structure. You can develop a proprietary formulation, and patent that. If you trial and get approved a specific formulation, that's what the patients will get, and their insurance carriers will pay through the nose. There are plenty of prescription drugs that are just fancy formulations of well known old compounds. That's not a scam-- the formulation will make or break a drug. It's the difference between a patient that walks out of the hospital versus leaving in a bag.
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#98 mag1
Posted 06 February 2015 - 10:50 PM The section quoted from the patent was looking for maximal doses. They were actively seeking out doses that would be toxic. These doses were much higher than those intended for therapeutic use. At the intended therapeutic dose, 3-BP was found to be non-toxic to the animals.
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Example 24: Determination of optimal dose, tumor response, toxicity and delay of tumor progression.

"All doses lower than 20 mM were well- tolerated and caused no deaths. In addition, there was no evidence of clinical distress (lack of appetite, urination, or significant change in body weight). Analysis of major organs (brain, lung, heart, liver, kidney, spleen, stomach, G.I, bladder and skeletal muscle) at necropsy confirmed the safety of these doses, as all were without any damage. These results therefore established the therapeutic dose of 3-bromopyruvate to be 2OmM or 16.8 mg/kg. In addition, an acute toxicity study was performed to determine the effects of 3- bromopyruvate administered FV. Based on the data acquired in rats, rabbits (2 animals per group followed for 1 week) were given 25 ml of 15, 20, and 25 mM 3-bromopyruvate as a single IV dose (i.e., using dose identified for rats). Results of the rabbit experiment paralleled those of the rats with 2OmM or 16.8 mg/kg 3-bromopyruvate calculated to be the therapeutic dose, with no evidence of any organ toxicity."

Figure 4 shows liver health improving after the 9th treatment.

It should be noted that the dose reported as safe (not clear what exact dose was used on the patient reported as 125 mg etc.) in the German report was 2-3.5 mg/kg.

The 3-BP treatment appeared from simple observation to be non-toxic and well tolerated. After the first round of dosing, the patient had no side-effects. The picture taken on his birthday shows what appears to be a happy and healthy person. No mention of pain medication is noted in the article.


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#99 pone11
Posted 06 February 2015 - 10:52 PM niner, on 06 Feb 2015 - 11:46 PM, said: Yeah, I think the toxicity of 3BP is non-trivial. Things like this are usually more toxic and less effective than they first appear, once they get into serious well-run trials with a lot of patients. As to the financial aspects of this, the Chinese product that's made in ton quantity is not a pharmaceutical grade. It's probably closer to what chemists call a "technical" grade, or maybe worse. If you want to go into humans, you need to develop a manufacturing method that is extremely clean. You can get a patent on the manufacturing method, if not the molecular structure. You can develop a proprietary formulation, and patent that. If you trial and get approved a specific formulation, that's what the patients will get, and their insurance carriers will pay through the nose. There are plenty of prescription drugs that are just fancy formulations of well known old compounds. That's not a scam-- the formulation will make or break a drug. It's the difference between a patient that walks out of the hospital versus leaving in a bag. Fine, but let's say that Chinese 3BP is technical grade and costs $125/ton. Along comes Group X that develops a proprietary process to make pharmaceutical grade 3BP at $1M / ton.
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Any competitor worth his salt goes to the Chinese and asks for a pharmaceutical grade at $500/ton, and I have no doubt they will get it.

Competition is a beautiful thing, when the free market is allowed to work.
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#100 mag1
Posted 06 February 2015 - 10:58 PM The cell toxicity studies with 3-BP showed no toxicity to normal cells over the range of therapeutic dosing used to destroy cancer cells.
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#101 niner
Posted 06 February 2015 - 11:03 PM pone11, on 06 Feb 2015 - 11:52 PM, said: Fine, but let's say that Chinese 3BP is technical grade and costs $125/ton. Along comes Group X that develops a proprietary process to make pharmaceutical grade 3BP at $1M / ton.
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Any competitor worth his salt goes to the Chinese and asks for a pharmaceutical grade at $500/ton, and I have no doubt they will get it.

Competition is a beautiful thing, when the free market is allowed to work. Competition and the free market are great, but they can't get blood from a turnip. The requirements for active pharmaceutical ingredients are incredibly tight. You even have to have a defined crystal morphology. There are great pharmaceutical firms in China that can do the job, but the kind of bulk producers who crank out 3BP for 125USD/ton aren't equipped to do it. There's a lot of competition and a free market in cars, for example, but I can't get that Tesla I want for five hundred bucks.
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#102 mag1
Posted 06 February 2015 - 11:17 PM The toxicity issue regarding 3-BP appears to be well considered in the patent and in the human report. When given in the range indicated for therapeutic use 3-BP
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did not appear to be toxic.

The main question that I am still unsure about is whether 3-BP is intended for systemic use. The patent and other sources seem unclear about this. There are many anti-cancer drugs that are effective when directly injected into a tumor. What patients really need is a systemically active treatment that could treat widely dispersed mets.

The metastatic melanoma patient report hinted that 3-BP would be effective as a systemic treatment. The patient was treated with an IV infusion of 3-BP.

It would be important to know whether either of the reported patients had wide spread metastatic illness. Perhaps these patients were selected on the basis of having huge tumor burdens that somehow were highly localized (for example, no brain mets etc.).
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#103 pone11
Posted 06 February 2015 - 11:26 PM mag1, on 06 Feb 2015 - 11:58 PM, said: The cell toxicity studies with 3-BP showed no toxicity to normal cells over the range of therapeutic dosing used to destroy cancer cells. You should work in marketing. Read your own rat study, which you quoted here:
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http://www.longecity...e-3#entry712248

"In order to determine the therapeutic dose of 3-bromopyruvate for intravenous (FV) administration, a dose-escalation study was conducted in normal Lewis rats (non-tumor bearing). Each group of animals (6 rats per group) received incremental doses of 3- bromopyruvate intravenously (2.5mL of 5, 10, 15, 20, 25 and 5OmM 3-bromopyruvate). The animals were observed for a period of 3 weeks and watched for any evidence of toxicity. The therapeutic dose was found to be 2OmM. At the highest dose of 5OmM, all the animals in the group died within 15 minutes. "

So in order to determine the "therapeutic dose" they tested different doses. Only after scaling the dose were they able to look back at the results and determine the therapeutic dose!!! That is all hindsight, not foresight. It was even more interesting in the rabbit study that you quoted in that same post, where "it was observed that the 5mM concentration of 3-bromopyruvate completely destroyed the tumor, but also caused widespread necrosis of the surrounding healthy liver resulting in the death of all the rabbits within the group."

Where has that scaled dosing procedure been done on human beings? It has not been done, right? The German cancer study was n=1. Therefore we do not know if the doses used on that 16 year old boy were the rabbit equivalent of 2.5 or 5mM concentrations. Therefore, it is impossible to know exactly what is a therapeutic dose for a human, and it is also impossible to say that the dose used on that boy did not kill healthy liver cells.

You don't need to defend the German doctors. It was a heroic effort to save a human life on a new therapy for which there are no human guidelines. The boy would have died sooner without the therapy.

Edited by pone11, 06 February 2015 - 11:27 PM.


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#104 pone11
Posted 06 February 2015 - 11:29 PM niner, on 07 Feb 2015 - 12:03 AM, said:
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pone11, on 06 Feb 2015 - 11:52 PM, said: Fine, but let's say that Chinese 3BP is technical grade and costs $125/ton. Along comes Group X that develops a proprietary process to make pharmaceutical grade 3BP at $1M / ton.

Any competitor worth his salt goes to the Chinese and asks for a pharmaceutical grade at $500/ton, and I have no doubt they will get it.

Competition is a beautiful thing, when the free market is allowed to work. Competition and the free market are great, but they can't get blood from a turnip. The requirements for active pharmaceutical ingredients are incredibly tight. You even have to have a defined crystal morphology. There are great pharmaceutical firms in China that can do the job, but the kind of bulk producers who crank out 3BP for 125USD/ton aren't equipped to do it. There's a lot of competition and a free market in cars, for example, but I can't get that Tesla I want for five hundred bucks.

I understand but a qualified company in the US buys the pharmaceutical grade from China, then tests for heavy metals, other contaminants, tests the concentration and purity, etc. Lousy manufacturers with a decent process and heavy quality assurance from a party who won't pass subgrade product can go far.

Once any chemical gets to this level of manufacturing volume, I think it is very very hard to control capitalism doing what capitalism always does:  increase supply and decrease prices, under relentless competition.
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#105 niner
Posted 06 February 2015 - 11:30 PM Well, if it's really non-toxic at therapeutic levels, then it should be perfect for systemic use. Toxicity is usually the dose-limiting effect in cancer therapy.
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#106 mag1
<p class="posted_info desc lighter ipsType_small">Posted 06 February 2015 - 11:42 PM Example 24 was trying to find the maximal dose. The patent has extensive documentation.
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For example, in  Example 17  Direct Intraarterial Injection of 3-BrPA into Liver Implanted VX2 Tumors Selectively Inhibits the Viability of Cells Therein without Altering the Viability of Surrounding Liver Tissue:

"...Animals treated identically, but not receiving 3-BrPA served as controls. Optimal results were obtained by delivering 25 ml 0.5 mM 3-BrPA, waiting 4 days, and then excising and subjecting each tumor, and the surrounding liver tissue, to histological analysis. The results obtained from this novel approach proved to be quite dramatic.

Compared to control "untreated" tumors, where representative sections (7 slides/tumor) obtained outside the central core region revealed nearly 100 % viable cells (Figure 2C), similarly located sections obtained from tumors treated with 3-BrPA (Figure 2D) contained almost all non- viable cells (nearly 100 % necrosis)."

This is a direct injection model. the dose used here was 25 ml 0.5 mM 3-BrPA. In the maximal dosing used in example 24, a 2.5 ml dose of 50mM was used which is 10 times higher than that used in example 17. It is known that at doses beyond the therapeutically intended range 3-BP would have serious toxicity. However, after receiving 9 treatments over a period of almost 1 year, the German patient had not demonstrated any toxicity. The scans shown in Figure 4 do not show evidence of such toxicity. The article noted that the liver was continuing to regenerate. The patient appeared happy and healthy on his birthday.


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#107 pone11
<p class="posted_info desc lighter ipsType_small">Posted 06 February 2015 - 11:49 PM mag1, on 07 Feb 2015 - 12:42 AM, said: Example 24 was trying to find the maximal dose. The patent has extensive documentation.
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For example, in  Example 17  Direct Intraarterial Injection of 3-BrPA into Liver Implanted VX2 Tumors Selectively Inhibits the Viability of Cells Therein without Altering the Viability of Surrounding Liver Tissue:

"...Animals treated identically, but not receiving 3-BrPA served as controls. Optimal results were obtained by delivering 25 ml 0.5 mM 3-BrPA, waiting 4 days, and then excising and subjecting each tumor, and the surrounding liver tissue, to histological analysis. The results obtained from this novel approach proved to be quite dramatic.

Compared to control "untreated" tumors, where representative sections (7 slides/tumor) obtained outside the central core region revealed nearly 100 % viable cells (Figure 2C), similarly located sections obtained from tumors treated with 3-BrPA (Figure 2D) contained almost all non- viable cells (nearly 100 % necrosis)."

This is a direct injection model. the dose used here was 25 ml 0.5 mM 3-BrPA. In the maximal dosing used in example 24, a 2.5 ml dose of 50mM was used which is 10 times higher than that used in example 17. It is known that at doses beyond the therapeutically intended range 3-BP would have serious toxicity. However, after receiving 9 treatments over a period of almost 1 year, the German patient had not demonstrated any toxicity. The scans shown in Figure 4 do not show evidence of such toxicity. The article noted that the liver was continuing to regenerate. The patient appeared happy and healthy on his birthday. But the actual dose calibration was in animals, and the dose for a human was an extrapolation from that. It's not the same as testing different doses in actual humans, and using statistics on a larger sample. I'm not saying you have to do that. I'm all for n=1. I'm all for dirty data. I'm saying you cannot rule out that they dosed too high and killed normal liver cells.

The point they make about not showing any toxicity is interesting, but this is their characterization. Toward the end they did find ascites, and there is no way to prove if these came from dead cancer cells or dead "normal" liver cells.

It is really remarkable that after nine treatments they claim no toxicity, but suddenly after one dose there is lethal toxicity? Either something doesn't add up there, or maybe the dose toxicity shifts over time as the primary cancer dies off. It looks like a tricky business.
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#108 mag1
<p class="posted_info desc lighter ipsType_small">Posted 06 February 2015 - 11:56 PM The patent is quoting state of the art treatment with 3-BP as of December 2006. Concerns about toxicity from 3-BP have been addressed by subsequent research.
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For example, the website of the company seeking to commercialize 3-BP notes the below research. Such research might help make 3-BP a patentable drug.

Clin Cancer Res. 2014 Dec 15;20(24):6406-17. doi: 10.1158/1078-0432.CCR-14-1271. Epub 2014 Oct 17. Systemic delivery of microencapsulated 3-bromopyruvate for the therapy of pancreatic cancer.

"...In vivo, animals treated with β-CD-3-BrPA demonstrated minimal or no tumor progression as evident by the BLI signal as opposed to animals treated with gemcitabine or the β-CD (60-fold and 140-fold signal increase, respectively). In contrast to animals treated with free 3-BrPA, no lethal toxicity was observed for β-CD-3-BrPA. CONCLUSION:

The microencapsulation of 3-BrPA represents a promising step towards achieving the goal of systemically deliverable antiglycolytic tumor therapy. The strong anticancer effects of β-CD-3-BrPA combined with its favorable toxicity profile suggest that clinical trials, particularly in patients with PDAC, should be considered."

Edited by mag1, 07 February 2015 - 12:24 AM.


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#109 pone11
<p class="posted_info desc lighter ipsType_small">Posted 07 February 2015 - 12:05 AM mag1, on 07 Feb 2015 - 12:56 AM, said: The patent is quoting state of the art treatment with 3-BP as of December 2006. Concerns about toxicity from 3-BP have been addressed by subsequent research.
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For example, the website of the company seeking to commercial 3-BP notes the below research. Such research might help make 3-BP a patentable drug.

Clin Cancer Res. 2014 Dec 15;20(24):6406-17. doi: 10.1158/1078-0432.CCR-14-1271. Epub 2014 Oct 17. Systemic delivery of microencapsulated 3-bromopyruvate for the therapy of pancreatic cancer.

"...In vivo, animals treated with β-CD-3-BrPA demonstrated minimal or no tumor progression as evident by the BLI signal as opposed to animals treated with gemcitabine or the β-CD (60-fold and 140-fold signal increase, respectively). In contrast to animals treated with free 3-BrPA, no lethal toxicity was observed for β-CD-3-BrPA. CONCLUSION:

The microencapsulation of 3-BrPA represents a promising step towards achieving the goal of systemically deliverable antiglycolytic tumor therapy. The strong anticancer effects of β-CD-3-BrPA combined with its favorable toxicity profile suggest that clinical trials, particularly in patients with PDAC, should be considered." We were talking about establishing therapeutic dosing for generic 3BP.  Now you change the topic to a proprietary version of 3BP.  That's not the conversation we were having.
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#110 mag1
<p class="posted_info desc lighter ipsType_small">Posted 07 February 2015 - 12:12 AM True, but different formulations of 3-BP have been in development for quite some time. Straight 3-BP is now 15 years old! The research into 3-BP since then has found even better formulations combinations etc.
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The encapsulated form of 3-BP noted in the article does not appear to require much technical expertise to prepare. It never seemed likely that a straight 3-BP product would be marketed.

Perhaps they will put it into minicells!

In addition to reformulations of 3BP there are also combinations which would allow for lower dosing of 3-BP (butyrate etc.).
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#111 resveratrol_guy
<p class="posted_info desc lighter ipsType_small">Posted 07 February 2015 - 11:31 AM It disturbs me that the therapeutic dose in rodents was found to be 20 mM, whereas 50 mM was rapidly fatal. That's a thin margin of safety -- so thin that we might need to abandon the concept of dose altogether, in favor of continual patient monitoring during administration.
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Then we have this issue of killing -- or not -- the surrounding healthy cells. Let's not confuse implanted vs. native tumors: the latter should have more precancerous cells surrounding them, due to the spatially continuous evolution of the tumor in situ. This could explain some of the contradictions between having no effect on healthy cells vs. killing the patient due to excessive "normal" cell death. (I use quotes because I suspect that these cells were actually partially glycolytic.)

I don't think it's bad that 3BP might kill these "swing cells", on their way to becoming cancer but not yet detectable as such. Again, it needs to come down to continual patient monitoring during administration.

"They will all struggle to manufacturer 'studies' that show that 3BP + <insert-poison-here> is 5% more effective than 3BP alone, and then use that fact to justify charging $100K more for the therapy." That would be hilarious, were it not so accurate. But this is the difference between Big Pharma and Big Pseudoscience: whereas Big Pharma overcharges for usally-trivial patentable differences in clinical outcome, Big Pseudoscience provides the most tested primal forms of the therapies, but is agnostic to evidence of efficacy and overcharges for the artisanal factor (e.g. soothing personal attention, aromatherapy in the lobby, organic juices, etc., hence the $28K). But at least we have a choice, and in this case, Big Pseudoscience is providing better options at present. International competition will certainly help.

@pone11: I would support your creation of a "lysis cancer scanner" thread, even if it only sits idle until its value and relevance become obvious years hence. It's too good an idea to get lost here.

As to all this tracking business, I propose a Cancer section, which in comparison to "Medicines & Diseases" (its parent) is actually a narrowly focussed topic. I've proposed this before.

I definitely would keep this thrad on 3BP alone. The existence of a Cancer section would draw the experts and critical thinkers that we need for potential breakthroughs of this magnitude, without muddying this thread, which is justifiably complex as it is.

If it helps, we could even have 2 subfolders: "Tumor-Specific Therapy" and "Broad-Based Therapy", or something more simply worded.
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#112 mag1
<p class="posted_info desc lighter ipsType_small">Posted 07 February 2015 - 01:01 PM The questions raised on the thread about toxicity are important. However, it should be understood that the patent is a highly detailed description of many instances of the use of 3-BP at many dosage ranges and with varying purposes in regard to describing aspects of treatment. After reading the patent in its entirety one realizes how non-toxic 3-BP treatment is when used in the manner described at the indicated therapeutic dosages for the selected purposes.
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It should be noted that in the below quote they are using 0.5 mM of 3-BP. In other parts of the patent they use 20, 25, and up to 50 mM 3-BP (that is the molarity used was up to 100 times higher). Yet, it needs to be clearly understood that the patent is describing various methods and dosages that are not directly comparable. For instance, the 2.5 ml of 20 mM 3-BP in example 24 was in the context of intravenous administration of the drug. Toxicity arose from this dosage scheme.

However, in example 17, 25 ml of .5 mM 3-BP injected intraarterially had a dramatic treatment effect with no detectable toxicity. It should be understood that directly targeting liver tumors in this way would presumably not expose other organs to the risk of toxicity arising from 3-BP treatment. In such a procedure there might be a method of actively diluting the 3-BP at the end of treatment, in order that no other organ would be exposed to concentrated 3-BP. Yet, once the blood supply was reopened rapid dilution would occur spontaneously once the 3-BP mixed with the blood. The so called TACE procedure (direct targeting of the liver) was used in the German report.

For Example,

"Example 17: Direct Intraarterial Injection of 3-BrPA into Liver Implanted VX2 Tumors Selectively Inhibits the Viability of Cells Therein without Altering the Viability of Surrounding Liver Tissue.

To test our hypothesis that direct intraarterial injection of a potent inhibitor of cell ATP production (3-BrPA) may selectively inhibit the viability of cells within the tumor, we employed the established VX2 tumor model for reasons described above. Small chunks of a donor VX2 tumor were minced, surgically implanted in the livers of 6 rabbits/experiment, and allowed to grow for 14 days (Figure 2A). At this time, the single well- delineated tumor that developed in each liver exhibited a high degree of arterial vascularization due to the onset of angiogenesis. After fasting the animals for 24 hours and administering anesthesia, a catheter was carefully inserted into the femoral artery and guided by fluoroscopy into the hepatic artery to a position near the tumor site (Figure 2B). Then, a single bolus injection of 3-BrPA was delivered in about 2 min directly into the artery. Animals treated identically, but not receiving 3-BrPA served as controls. Optimal results were obtained by delivering 25 ml 0.5 mM 3-BrPA, waiting 4 days, and then excising and subjecting each tumor, and the surrounding liver tissue, to histological analysis. The results obtained from this novel approach proved to be quite dramatic.

Compared to control "untreated" tumors, where representative sections (7 slides/tumor) obtained outside the central core region revealed nearly 100 % viable cells (Figure 2C), similarly located sections obtained from tumors treated with 3-BrPA (Figure 2D) contained almost all non- viable cells (nearly 100 % necrosis). Viable tumor cells were detected only in small areas near arteries feeding the tumors (Figure 2E), and at the tumor periphery where sinusoidal blood is available. This may reflect more active mitochondria in these oxygen rich environments that are not completely debilitated at the concentrations of 3- BrPA used. Significantly, no damage occurred to liver tissue surrounding tumors that had been treated with 3-BrPA (Figures 2F and 2G). These results, reproduced in a number of experiments, were subjected to statistical evaluation. Tumors untreated with 3-BrPA (controls) contain 74 ± 5% viable cells in the entire population (Figure 2H, 1st column). The remaining cells, located within the hypoxic tumor core, have already become non-viable, a common feature of rapidly growing solid tumors. Treatment with a single intraarterial injection of 3-BrPA decreases the number of viable cells to 16 ± 5% (Figure 2H, 2nd column), thus increasing the total number of nonviable cells in the population to 84 ± 5% (P< 0.05). The maximal number of non-viable cells observed in any one experiment was 90%. In sharp contrast, the surrounding liver tissue remained completely viable in all cases examined (Figure 2H, 3rd and 4th columns)."


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#113 mag1
<p class="posted_info desc lighter ipsType_small">Posted 07 February 2015 - 02:51 PM The treatment with 3-BP in the German report did not appear to result in observable direct liver toxicity. Throughout the article statements by the authors make clear strong claims of the safety and non-toxicity of 3-BP when used in this human patient at the dosage indicated and with the particular method of administration used.
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For example,

In the Introduction, "In addition, 3BP at its effective concentrations that kill cancer cells has little or no effect on normal cells"

In the Conclusion, "A patented and proprietary formulation of 3BP is safe at the concentrations (2–3.5 mg/kg body weight) employed for TACE delivery in humans. No major cyto-toxicities of this specially formulated 3BP have been observed. Please note that unformulated 3BP may be harmful in some cases."

"Liver regeneration is not inhibited by 3BP treatment."

While further noting,

"Careful monitoring of blood ammonia, uric acid, and urea levels is paramount during 3BP treatment."

"The levels of albumin and billirubins are also important parameters in assessing liver functions and in predicting a patient’s survival during 3BP treatment."

These statements by a team of medical experts should not be dismissed lightly. As their claims are based on very comprehensive monitoring of the patient. The researchers carefully monitored a variety of measurements that would indicate liver toxicity:

"at first presentation and his blood chemistry revealed high values of the liver enzymes alanine transaminase (ALT), aspartate transaminase (AST), and gamma glutamyl transpeptidase (GGT), indicating liver abnormality / damage. "

[This liver damage was before the start of 3-BP treatment. They also performed a pre-3BP liver biopsy, MRI, CT, echo imaging, and PET scan.) Additionally, they monitored ammonia, uric acid and urea levels.

Furthermore, the article notes that the nature of the TLS in this instance presented atypically. This discrepancy in TLS might possibly offer insight into the patient's demise. If the widely accepted indicators of TLS "uric acid, potassium, and phosphorus in other cancers." did not apply in the patient's particular form of liver cancer (FLC), they might have been targeting the treatment response to the wrong biomarker.

"As indicated in Fig. 3b, ammonia levels fluctuated more than those of urea and uric acid during 3BP treatment. This is very interesting as FLC is eosinophilic which is indicative of a higher content of cellular protein than of nucleic acids. Therefore, it is suggested that the rise in blood ammonia following 3BP treatment was due to FLC cell death, releasing considerable amounts of cellular proteins. This elevation of blood ammonia may be characteristic of TLS of FLC as TLS is generally diagnosed by acute elevations of uric acid, potassium, and phosphorus in other cancers."

The significance of urea level measurement is revealed in the below quote.

"The urea level was low (Fig. 3b, pink graph),an average of 5 mM, indicating a still functioning nitrogen detoxification of the liver and kidneys."

It is fair to say that the patient received a very high standard of care.

Further, since this is the initial landmark case of 3-BP treatment in humans, it would be expected that if the treatment were found in some way to have been deficient, then it likely would not have been published. There might have been patients treated with 3-BP who did not have such a dramatic success as the German report. Such negative patient reports have not been published.

Toxicity of 3-BP treatment would likely be obvious, immediate and cumulative. In the animal studies, the toxicity caused by 3-BP was measurable within days (or a week or two of treatment(in some instances after a single injection)). 3-BP shuts down cellular respiration within minutes, and then rapidly degrades in the body. Any damage from treatment would occur quickly. In the human report, large initial doses were used and then the treatment was gradually scaled back. After a year of such treatment, any toxicity from 3-BP should have been observable. Toxicity would be expected through time to deplete the patient. However, the patient report describes a patient who during the year of treatment appeared to be progressively recovering. The one notable mention of liver toxicity in the report was toxicity existing prior to the start of 3-BP treatment (possibly caused by the tumor or the other chemotherapeutic drugs).
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#114 mag1
<p class="posted_info desc lighter ipsType_small">Posted 07 February 2015 - 03:11 PM The question of toxicity has diverted attention from my main concern about 3-BP treatment, namely the range of cancers which 3-BP could be used to treat.
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The 3-BP patent that we have been considering regarding the toxicity of 3-BP is mostly concerned with intra-arterial administration of 3-BP to liver cancers. This is a highly specific cancer indication. Much of the patent is not making wide ranging claims that 3-BP could safely treat all cancers. Shutting off the blood supply to the liver and directly injecting 3-BP into an occluded artery avoids exposing other organs to toxicity and maximizes the potential of success of 3-BP treatment. This so called TACE procedure was the method of 3-BP in the German report. The positive results noted with 3-BP in intra-arterial administration to the liver might have no application to a broader range of cancers.

Safe and effective 3-BP treatment of patients with widespread metastatic illness would be the real breakthrough. It is not clear whether such a human patient report has yet been published.
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#115 pone11
<p class="posted_info desc lighter ipsType_small">Posted 07 February 2015 - 03:13 PM resveratrol_guy, on 07 Feb 2015 - 12:31 PM, said: It disturbs me that the therapeutic dose in rodents was found to be 20 mM, whereas 50 mM was rapidly fatal. That's a thin margin of safety -- so thin that we might need to abandon the concept of dose altogether, in favor of continual patient monitoring during administration.
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Then we have this issue of killing -- or not -- the surrounding healthy cells. Let's not confuse implanted vs. native tumors: the latter should have more precancerous cells surrounding them, due to the spatially continuous evolution of the tumor in situ. This could explain some of the contradictions between having no effect on healthy cells vs. killing the patient due to excessive "normal" cell death. (I use quotes because I suspect that these cells were actually partially glycolytic.)

I don't think it's bad that 3BP might kill these "swing cells", on their way to becoming cancer but not yet detectable as such. Again, it needs to come down to continual patient monitoring during administration. This is exactly the right point:  even once you establish a therapeutic dose, you have to continually monitor for lysis and tissue death, and then you need to adjust dose and spacing.

What I don't understand is how do you monitor for death of healthy tissue? In case of the liver patient, they had liver markers that were going bad at the end of treatment. I guess we lost an opportunity there to see how adjusting the dose down might have improved outcome. It's also very bad that they didn't autopsy his liver and try to determine if there was necrosis of healthy tissue.
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#116 pone11
<p class="posted_info desc lighter ipsType_small">Posted 07 February 2015 - 03:15 PM mag1, on 07 Feb 2015 - 2:01 PM, said: The questions raised on the thread about toxicity are important. However, it should be understood that the patent is a highly detailed description of many instances of the use of 3-BP at many dosage ranges and with varying purposes in regard to describing aspects of treatment. After reading the patent in its entirety one realizes how non-toxic 3-BP treatment is when used in the manner described at the indicated therapeutic dosages for the selected purposes.
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It should be noted that in the below quote they are using 0.5 mM of 3-BP. In other parts of the patent they use 20, 25, and up to 50 mM 3-BP (that is the molarity used was up to 100 times higher). Yet, it needs to be clearly understood that the patent is describing various methods and dosages that are not directly comparable. For instance, the 2.5 ml of 20 mM 3-BP in example 24 was in the context of intravenous administration of the drug. Toxicity arose from this dosage scheme.

However, in example 17, 25 ml of .5 mM 3-BP injected intraarterially had a dramatic treatment effect with no detectable toxicity. It should be understood that directly targeting liver tumors in this way would presumably not expose other organs to the risk of toxicity arising from 3-BP treatment. In such a procedure there might be a method of actively diluting the 3-BP at the end of treatment, in order that no other organ would be exposed to concentrated 3-BP. Yet, once the blood supply was reopened rapid dilution would occur spontaneously once the 3-BP mixed with the blood. The so called TACE procedure (direct targeting of the liver) was used in the German report.

For Example,

"Example 17: Direct Intraarterial Injection of 3-BrPA into Liver Implanted VX2 Tumors Selectively Inhibits the Viability of Cells Therein without Altering the Viability of Surrounding Liver Tissue." Implanted tumors are a bad model to use to determine the amount of damage done to "normal" cells around the cancer. The cancer has not had time to integrate completely into tissues the way a naturally occurring tumor does.
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#117 mag1
<p class="posted_info desc lighter ipsType_small">Posted 07 February 2015 - 03:21 PM In the article,
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Advanced cancers: eradication in all cases using 3-bromopyruvate therapy to deplete ATP

Biochemical and Biophysical Research Communications 324 (2004) 269–275

Figure 1C shows that a dosage of up to 0.06 mM 3-BP had no effect on cell viability of normal hepatocytes, whereas at 0.03 - 0.06 mM 3-BP there was 90% tumor cell destruction. All the animals in the article receiving direct injections of 3-BP recovered.
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#118 pone11
<p class="posted_info desc lighter ipsType_small">Posted 07 February 2015 - 03:25 PM mag1, on 07 Feb 2015 - 3:51 PM, said: The treatment with 3-BP in the German report did not appear to result in observable direct liver toxicity. Throughout the article statements by the authors make clear strong claims of the safety and non-toxicity of 3-BP when used in this human patient at the dosage indicated and with the particular method of administration used.
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For example,

In the Introduction, "In addition, 3BP at its effective concentrations that kill cancer cells has little or no effect on normal cells"

In the Conclusion, "A patented and proprietary formulation of 3BP is safe at the concentrations (2–3.5 mg/kg body weight) employed for TACE delivery in humans. No major cyto-toxicities of this specially formulated 3BP have been observed. Please note that unformulated 3BP may be harmful in some cases."

"Liver regeneration is not inhibited by 3BP treatment."

While further noting,

"Careful monitoring of blood ammonia, uric acid, and urea levels is paramount during 3BP treatment."

"The levels of albumin and billirubins are also important parameters in assessing liver functions and in predicting a patient’s survival during 3BP treatment."

These statements by a team of medical experts should not be dismissed lightly. As their claims are based on very comprehensive monitoring of the patient. The researchers carefully monitored a variety of measurements that would indicate liver toxicity:

"at first presentation and his blood chemistry revealed high values of the liver enzymes alanine transaminase (ALT), aspartate transaminase (AST), and gamma glutamyl transpeptidase (GGT), indicating liver abnormality / damage. "

[This liver damage was before the start of 3-BP treatment. They also performed a pre-3BP liver biopsy, MRI, CT, echo imaging, and PET scan.) Additionally, they monitored ammonia, uric acid and urea levels.

Furthermore, the article notes that the nature of the TLS in this instance presented atypically. This discrepancy in TLS might possibly offer insight into the patient's demise. If the widely accepted indicators of TLS "uric acid, potassium, and phosphorus in other cancers." did not apply in the patient's particular form of liver cancer (FLC), they might have been targeting the treatment response to the wrong biomarker.

"As indicated in Fig. 3b, ammonia levels fluctuated more than those of urea and uric acid during 3BP treatment. This is very interesting as FLC is eosinophilic which is indicative of a higher content of cellular protein than of nucleic acids. Therefore, it is suggested that the rise in blood ammonia following 3BP treatment was due to FLC cell death, releasing considerable amounts of cellular proteins. This elevation of blood ammonia may be characteristic of TLS of FLC as TLS is generally diagnosed by acute elevations of uric acid, potassium, and phosphorus in other cancers."

The significance of urea level measurement is revealed in the below quote.

"The urea level was low (Fig. 3b, pink graph),an average of 5 mM, indicating a still functioning nitrogen detoxification of the liver and kidneys."

It is fair to say that the patient received a very high standard of care.

Further, since this is the initial landmark case of 3-BP treatment in humans, it would be expected that if the treatment were found in some way to have been deficient, then it likely would not have been published. There might have been patients treated with 3-BP who did not have such a dramatic success as the German report. Such negative patient reports have not been published.

Toxicity of 3-BP treatment would likely be obvious, immediate and cumulative. In the animal studies, the toxicity caused by 3-BP was measurable within days (or a week or two of treatment(in some instances after a single injection)). 3-BP shuts down cellular respiration within minutes, and then rapidly degrades in the body. Any damage from treatment would occur quickly. In the human report, large initial doses were used and then the treatment was gradually scaled back. After a year of such treatment, any toxicity from 3-BP should have been observable. Toxicity would be expected through time to deplete the patient. However, the patient report describes a patient who during the year of treatment appeared to be progressively recovering. The one notable mention of liver toxicity in the report was toxicity existing prior to the start of 3-BP treatment (possibly caused by the tumor or the other chemotherapeutic drugs). You already posted all of this and we responded to it. Rather than responding to the issues we raised, you just repost the same facts again. Why do that? That doesn't improve a thread to have you ignore points other people make and just repeat things. You are just making the thread unnecessarily longer without adding content.

I responded to these facts here:

http://www.longecity...ndpost&p=712283

We have no human studies to determine therapeutic doses. Therefore we have no way to know if the dose the German boy was destroying healthy tissue in addition to cancerous tissue. The fact that the doctors deny this isn't proof that it is so. There was no autopsy on the liver.

I suppose that 3BP could have one safe dose at the beginning, and then maybe there is some accumulative effect that requires dose adjustment later. All of that has yet to be figured out.

Edited by pone11, 07 February 2015 - 03:26 PM.


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#119 pone11
<p class="posted_info desc lighter ipsType_small">Posted 07 February 2015 - 03:38 PM mag1, on 07 Feb 2015 - 4:21 PM, said: In the article,
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Advanced cancers: eradication in all cases using 3-bromopyruvate therapy to deplete ATP

Biochemical and Biophysical Research Communications 324 (2004) 269–275

Figure 1C shows that a dosage of up to 0.06 mM 3-BP had no effect on cell viability of normal hepatocytes, whereas at 0.03 - 0.06 mM 3-BP there was 90% tumor cell destruction. All the animals in the article receiving direct injections of 3-BP recovered. Can you start publishing full text links to your studies? It really helps people out, and this thread has value for people so maintaining quality is important. Full text to your study is here:

http://www.sciencedi...006291X04020625

It looks like these were subcutaneous tumors. They were therefore not well integrated into vital organs of the body.

That would be a poor model for evaluating how 3BP might kill "normal" cells that are adjacent to a cancer. As resveratrol_guy correctly points out, many of those "normal" cells are probably in some pre-cancerous state and have been made glycolytic, thus subject to the actions of 3BP. So treating something like a late stage liver cancer becomes extremely treacherous.

Rather than reflexively posting every study with a "therapeutic" dose, you should acknowledge the rabbit and mouse studies you posted, referenced in my post here:

http://www.longecity...e-4#entry712283

This finding that there are doses of 3BP that kill "normal" cells adjacent to a cancer is important. You shouldn't keep trying to bury it. Rather we should acknowledge:

1) We don't know the full extent of dose toxicity in humans, yet.

2) This toxicity on adjacent cells may be different:

a) in different cancers

b) in different stages of a cancer

c) in different patients based on biology

I think resveratrol_guy made the right point:  we need to develop methods for evaluating when this necrosis of "normal" tissue is happening, and the dose or spacing then needs adjustment. The point is ANY dose that remains fixed is probably the wrong approach. Rather, this is a drug that requires a very interactive methodology:  adjusting dose to the toxic effects measured after administering a dose.

My question is how would you do this in a liver cancer? Would it require you to constantly take biopsies of the liver tissue? That hardly seems practical, and it would probably be pretty dangerous if repeated too often.

Edited by pone11, 07 February 2015 - 03:41 PM.


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Advert:Advertise on LongeCity===#120 mag1=== <p class="posted_info desc lighter ipsType_small">Posted 07 February 2015 - 03:57 PM
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I am becoming somewhat confused by the argument.

The noted quote from the patent used dosages of 20mM and 50mM etc. intravenously.

The German patient received intra-arterial treatment. The description in the patent did not find toxicity in animals when they were treated with 3-BP using the optimal intra-arterial liver protocol.

"Rabbits treated with 25mL of 1.75 mM 3-bromopyruvate had 100% tumor cell destruction without any damage to the normal liver"

The medical experts in the German report used a wide range of biomarkers to assess liver toxicity. Liver toxicity was not found. In light of the evidence presented in the article, I do not understand why the possibility of liver toxicity continues to be suggested.

In fact, the article notes "Regeneration of liver tissue was also observed and the data are being analyzed for future publication." The authors claim they have direct evidence that the liver was recovering and perhaps they could also show that 3-BP treatment did not cause toxicity. Liver biopsy likely was performed during 3-BP treatment (as might be expected).