17 replies to this topic

[ppp]

As I've mentioned here in the past, my son has osteosarcoma (bone cancer). In addition to conventional treatment I've been giving him curcumin, resveratrol, quercetin and omega-3 as a combination. The resveratrol dose has been 1 Revgenetics LiCap twice a day. The latest scan shows the tumour growing fast. I want to up the dose considerably, and was going to go for 4 LiCaps twice a day. My questions are:

1. Has anyone else tried this dosage?

2. Is it better to go for two divided doses, as I have been, or would one big dose be better?

Please, any advice or experiences you have would be gratefully received.

Thanks

[maxwatt]

As I've mentioned here in the past, my son has osteosarcoma (bone cancer). In addition to conventional treatment I've been giving him curcumin, resveratrol, quercetin and omega-3 as a combination. The resveratrol dose has been 1 Revgenetics LiCap twice a day. The latest scan shows the tumour growing fast. I want to up the dose considerably, and was going to go for 4 LiCaps twice a day. My questions are:

1. Has anyone else tried this dosage?

2. Is it better to go for two divided doses, as I have been, or would one big dose be better?

Please, any advice or experiences you have would be gratefully received.

Thanks

1. The dose of resveratrol is reasonably safe, well within the limits of what hs been used in ongoing human trials of resveratrol, where the dose has been typically 2.5 and 5 grams in a similar dispersant as used in the LiCaps. The Tween 80 used as a "carrier" is probably also safe at that dose, well withing FDA guidelines. Anthony should speak to the issue of the maximum dosage of this product. You may want to consider even larger doses, and look into obtaining resveratrol in powder form, both for economy and to be able to administer larger doses.

2. Higher blood levels were found in humans with morning administration in Boocock's pharmokinetic study, and resveratrol is known to interact with CLK-1 and the body's diurnal cycles. Morning administration is best, IMO. In the case of a disease therapy, no one knows the ideal timing or method of administration. No studies have been done in humans, and the cancer research has been in vitro. Higher levels of resveratrol seem to be more effective and even necessary, and this would argue for one large dose over multiple doses to obtain the same daily dose.

Zerumbone, a chemical extracted from a tropical ginger plant, has been shown to be effective against osteosarcoma in a test-tube, and I believe in rat models. Email or PM me if you want to discuss.

[niner]

I agree with maxwatt's comments, and just wanted to add that there is evidence from human pharmacokinetic studies that says you will get a higher AUC, meaning better overall blood levels, if you take it all in one dose. This would hold for doses up to about a gram and a half. In a high dose regime (2-5 grams) I would consider twice a day dosing. The amount of resveratrol you are using, 500mg/day, is well under the human trial doses (2.5-5g). You really have a lot of dosing flexibility here, and under the circumstances I would go a lot higher. The anti-cancer properties of resveratrol are tied to its ability to induce apoptosis, and that is dose-related. At low doses, resveratrol suppresses apoptosis, while at high doses it enhances apoptosis. You want it to be enhanced in this case, so you should go high.

I wish you all the best in your efforts.

[Lufega]

With Curcumin, a large once a day dose is better. Dump the pills and buy the sabinsa C3 powder. Aim for a dose of 4-8 grams. 15-20 minutes prior to using curcumin, take 1 gram of quercetin. This will prevent the liver from metabolizing the curcumin into unusable forms.

[tunt01]

out of curiosity, how old is your son and how much does he weigh (in kilograms)? just want to make sure people aren't confusing dose levels for an adult male (160 lbs.) and the child is like 50 lbs...

[niner]

out of curiosity, how old is your son and how much does he weigh (in kilograms)? just want to make sure people aren't confusing dose levels for an adult male (160 lbs.) and the child is like 50 lbs...

Good point. We should be discussing dosage in mg/kg (milligrams per kilogram) 1kg = 2.2 lb, 1 gram = 1000 mg.

[niner]

ppp, do you know which type of cell is at the root of your child's osteosarcoma? Or anything about receptor characteristics of it? If it happened to be acutely sensitive to BMP-2, then resveratrol might need a rethink. According to this paper, resveratrol upregulates BMP-2, which acts to encourage bone formation. I suspect that the pro-apoptotic effect of resveratrol would substantially outweigh this, but I'd be remiss not to mention it.

[ppp]

out of curiosity, how old is your son and how much does he weigh (in kilograms)? just want to make sure people aren't confusing dose levels for an adult male (160 lbs.) and the child is like 50 lbs...

He's just turned 16 and weighs just over 50kg.

[ppp]

ppp, do you know which type of cell is at the root of your child's osteosarcoma? Or anything about receptor characteristics of it? If it happened to be acutely sensitive to BMP-2, then resveratrol might need a rethink. According to this paper, resveratrol upregulates BMP-2, which acts to encourage bone formation. I suspect that the pro-apoptotic effect of resveratrol would substantially outweigh this, but I'd be remiss not to mention it.

It's an osteoblastic osteosarcoma rather than one of the other sub-types. MG-63, which is the cell type used in that paper is osteoblastic, which is a worry. But there are other papers that look specifically at osteosarcoma and resveratrol - such as this one, which conclude that resveratrol has an apoptopic effect on a range of osteoblastic osteosarcoma cell lines. Damn but this is worrying...

[ppp]

1. The dose of resveratrol is reasonably safe, well within the limits of what hs been used in ongoing human trials of resveratrol, where the dose has been typically 2.5 and 5 grams in a similar dispersant as used in the LiCaps. The Tween 80 used as a "carrier" is probably also safe at that dose, well withing FDA guidelines. Anthony should speak to the issue of the maximum dosage of this product. You may want to consider even larger doses, and look into obtaining resveratrol in powder form, both for economy and to be able to administer larger doses.

2. Higher blood levels were found in humans with morning administration in Boocock's pharmokinetic study, and resveratrol is known to interact with CLK-1 and the body's diurnal cycles. Morning administration is best, IMO. In the case of a disease therapy, no one knows the ideal timing or method of administration. No studies have been done in humans, and the cancer research has been in vitro. Higher levels of resveratrol seem to be more effective and even necessary, and this would argue for one large dose over multiple doses to obtain the same daily dose.

Zerumbone, a chemical extracted from a tropical ginger plant, has been shown to be effective against osteosarcoma in a test-tube, and I believe in rat models. Email or PM me if you want to discuss.

I've gone for the LiCaps because I assumed you would get a higher AUC for a lower dose.

In the case of a morning dose, is this with or without food? At the moment he's having EGCG first thing, on an empty stomach, along with quercetin. Do you think the rsv should be taken at the same time or 30 mins later with some breakfast?

[maxwatt]

1. The dose of resveratrol is reasonably safe, well within the limits of what hs been used in ongoing human trials of resveratrol, where the dose has been typically 2.5 and 5 grams in a similar dispersant as used in the LiCaps. The Tween 80 used as a "carrier" is probably also safe at that dose, well withing FDA guidelines. Anthony should speak to the issue of the maximum dosage of this product. You may want to consider even larger doses, and look into obtaining resveratrol in powder form, both for economy and to be able to administer larger doses.

2. Higher blood levels were found in humans with morning administration in Boocock's pharmokinetic study, and resveratrol is known to interact with CLK-1 and the body's diurnal cycles. Morning administration is best, IMO. In the case of a disease therapy, no one knows the ideal timing or method of administration. No studies have been done in humans, and the cancer research has been in vitro. Higher levels of resveratrol seem to be more effective and even necessary, and this would argue for one large dose over multiple doses to obtain the same daily dose.

Zerumbone, a chemical extracted from a tropical ginger plant, has been shown to be effective against osteosarcoma in a test-tube, and I believe in rat models. Email or PM me if you want to discuss.

I've gone for the LiCaps because I assumed you would get a higher AUC for a lower dose.

In the case of a morning dose, is this with or without food? At the moment he's having EGCG first thing, on an empty stomach, along with quercetin. Do you think the rsv should be taken at the same time or 30 mins later with some breakfast?

I recall a study which found higher serum levels taken without food; this was for plain resveratrol, not the LiCaps.

[ppp]

With Curcumin, a large once a day dose is better. Dump the pills and buy the sabinsa C3 powder. Aim for a dose of 4-8 grams. 15-20 minutes prior to using curcumin, take 1 gram of quercetin. This will prevent the liver from metabolizing the curcumin into unusable forms.

Thanks.

[niner]

ppp, do you know which type of cell is at the root of your child's osteosarcoma? Or anything about receptor characteristics of it? If it happened to be acutely sensitive to BMP-2, then resveratrol might need a rethink. According to this paper, resveratrol upregulates BMP-2, which acts to encourage bone formation. I suspect that the pro-apoptotic effect of resveratrol would substantially outweigh this, but I'd be remiss not to mention it.

It's an osteoblastic osteosarcoma rather than one of the other sub-types. MG-63, which is the cell type used in that paper is osteoblastic, which is a worry. But there are other papers that look specifically at osteosarcoma and resveratrol - such as this one, which conclude that resveratrol has an apoptopic effect on a range of osteoblastic osteosarcoma cell lines. Damn but this is worrying...

Yes, it worried me as well. The ovarectomized rat is a model for a post-menopausal female, so we don't know the relevance to a young male osteosarcoma patient. In http://pmid.us/18838962 they found that treating an in vitro OS model with BMP resulted in tumor growth rather than bone formation. Again, it's hard to say what to make of the relevance of this, being an in vitro model where they simply added BMPs. The most relevant work I found on this question is the following paper, which is actually looking at human cases of OS in a reasonably-powered study. They find no relationship between BMP expression and either survival or response to chemotherapy. This result makes me worry a lot less.

J Clin Pathol. 2002 May;55(5):381-5. Free Full Text
The expression of bone morphogenetic proteins in osteosarcoma and its relevance as a prognostic parameter.
Sulzbacher I, Birner P, Trieb K, Pichlbauer E, Lang S.

Clinical Institute of Pathology, University of Vienna, Medical School, Waehringer Guertel 18-20, A-1090 Vienna, Austria. irene.sulzbacher@akh-wien.ac.at

AIMS: The expression of bone morphogenetic proteins (BMPs) was analysed in 47 osteosarcomas to determine differences in the expression of BMP subtypes and to correlate expression with response to chemotherapy, in addition to the disease free and overall survival of patients. METHODS: The expression of BMPs was examined immunohistochemically in 47 biopsy specimens of osteosarcoma using commercially available antibodies against different subtypes (BMP-2/4 (A-20), BMP-3 (N-19), BMP-4 (N-19), BMP-5 (N-19), BMP-6 (N-19), BMP-7 (N-19), BMP-8 (N-19)). The avidin-biotin-immunoperoxidase method was used for all antibodies. RESULTS: The expression of BMP subtypes varied considerably: 28 of the 47 tumours expressed BMP-2/4, 24 expressed BMP-3, 41 expressed BMP-5, 31 expressed BMP-6, 43 expressed BMP-7, and 42 expressed BMP-8. High expression of BMP-6 was found in those parts of the osteosarcoma with a chondroid differentiation (p = 0.016, Mann-Whitney test). No correlation was observed between the response to chemotherapy and the expression of BMPs (p > 0.05, Mann-Whitney test). Univariate analysis showed no correlation between overall survival or progression free survival and the expression of BMPs (p > 0.05, log rank test). CONCLUSIONS: BMP-7 and BMP-8 are highly expressed in osteosarcoma. Moreover, high expression of BMP-6 correlates with a chondroid differentiation. In contrast to conclusions derived from previous studies in which small numbers of tumours were investigated, these results indicate that the expression of BMPs does not help to predict the outcome of patients.

PMID: 11986346

[ppp]

ppp, do you know which type of cell is at the root of your child's osteosarcoma? Or anything about receptor characteristics of it? If it happened to be acutely sensitive to BMP-2, then resveratrol might need a rethink. According to this paper, resveratrol upregulates BMP-2, which acts to encourage bone formation. I suspect that the pro-apoptotic effect of resveratrol would substantially outweigh this, but I'd be remiss not to mention it.

It's an osteoblastic osteosarcoma rather than one of the other sub-types. MG-63, which is the cell type used in that paper is osteoblastic, which is a worry. But there are other papers that look specifically at osteosarcoma and resveratrol - such as this one, which conclude that resveratrol has an apoptopic effect on a range of osteoblastic osteosarcoma cell lines. Damn but this is worrying...

Yes, it worried me as well. The ovarectomized rat is a model for a post-menopausal female, so we don't know the relevance to a young male osteosarcoma patient. In http://pmid.us/18838962 they found that treating an in vitro OS model with BMP resulted in tumor growth rather than bone formation. Again, it's hard to say what to make of the relevance of this, being an in vitro model where they simply added BMPs. The most relevant work I found on this question is the following paper, which is actually looking at human cases of OS in a reasonably-powered study. They find no relationship between BMP expression and either survival or response to chemotherapy. This result makes me worry a lot less.

J Clin Pathol. 2002 May;55(5):381-5. Free Full Text
The expression of bone morphogenetic proteins in osteosarcoma and its relevance as a prognostic parameter.
Sulzbacher I, Birner P, Trieb K, Pichlbauer E, Lang S.

Clinical Institute of Pathology, University of Vienna, Medical School, Waehringer Guertel 18-20, A-1090 Vienna, Austria. irene.sulzbacher@akh-wien.ac.at

AIMS: The expression of bone morphogenetic proteins (BMPs) was analysed in 47 osteosarcomas to determine differences in the expression of BMP subtypes and to correlate expression with response to chemotherapy, in addition to the disease free and overall survival of patients. METHODS: The expression of BMPs was examined immunohistochemically in 47 biopsy specimens of osteosarcoma using commercially available antibodies against different subtypes (BMP-2/4 (A-20), BMP-3 (N-19), BMP-4 (N-19), BMP-5 (N-19), BMP-6 (N-19), BMP-7 (N-19), BMP-8 (N-19)). The avidin-biotin-immunoperoxidase method was used for all antibodies. RESULTS: The expression of BMP subtypes varied considerably: 28 of the 47 tumours expressed BMP-2/4, 24 expressed BMP-3, 41 expressed BMP-5, 31 expressed BMP-6, 43 expressed BMP-7, and 42 expressed BMP-8. High expression of BMP-6 was found in those parts of the osteosarcoma with a chondroid differentiation (p = 0.016, Mann-Whitney test). No correlation was observed between the response to chemotherapy and the expression of BMPs (p > 0.05, Mann-Whitney test). Univariate analysis showed no correlation between overall survival or progression free survival and the expression of BMPs (p > 0.05, log rank test). CONCLUSIONS: BMP-7 and BMP-8 are highly expressed in osteosarcoma. Moreover, high expression of BMP-6 correlates with a chondroid differentiation. In contrast to conclusions derived from previous studies in which small numbers of tumours were investigated, these results indicate that the expression of BMPs does not help to predict the outcome of patients.

PMID: 11986346

Thanks for taking the time to follow that up. It is more reassuring, but there is always the fear of doing harm not good. It's scary but our treatment options are running out fast.

[ppp]

Thanks all for your comments. I'd still be grateful for some more information regarding the bioavailability of the LiCaps versus non-micronised powders.

This is what I think gives the best option for the moment:

Morning (on an empty stomach): EGCG (600 mg) + Quercetin (1.6 gm) + Bromelain, followed 15-20 mins later by 8 LiCaps (2 gm). Wait at least 30m minutes before food.

Daytime: Selenite (1 mg), D3 (10000 IU), Black seed oil, 2 x Optiberry 30 mg, 2 x ActivaMune (bioavailable DIM)

Night (on an empty stomach): EGCG (600 mg) + Quercetin (1.6 gm) + Bromelain, followed 15-20 mins later by 8 gm of LongVida (bioavailable curcumin).

Anyone care to comment on this?

Thanks.

[niner]

Thanks all for your comments. I'd still be grateful for some more information regarding the bioavailability of the LiCaps versus non-micronised powders.

I believe that what is known about it comes from a Sirtris patent and/or presentation, though I've lost track of the data. Perhaps someone else will have it. (maxwatt? Anthony?) I'm of the opinion that the AUC (Area Under the Curve of plasma concentration vs time) is more important than the Cmax (maximal concentration; peak of the curve). The Cmax is very transitory while the AUC represents total body exposure to the drug. Formulation of resveratrol tends to have a bigger effect on the Cmax than it does on AUC, so in making comparisons, try to keep in mind which parameter it is. My recollection is that Cmax improved by somewhat less than a factor of ten, and AUC was a fair amount less good than that. The formulation used in animal experiments is should be reported, but often is not.

Morning (on an empty stomach): EGCG (600 mg) + Quercetin (1.6 gm) + Bromelain, followed 15-20 mins later by 8 LiCaps (2 gm). Wait at least 30m minutes before food.

Daytime: Selenite (1 mg), D3 (10000 IU), Black seed oil, 2 x Optiberry 30 mg, 2 x ActivaMune (bioavailable DIM)

Night (on an empty stomach): EGCG (600 mg) + Quercetin (1.6 gm) + Bromelain, followed 15-20 mins later by 8 gm of LongVida (bioavailable curcumin).

It looks good. The resveratrol dose at ~40mg/kg should be within the pro-apoptotic range (at least for ischemic rat myocardium) according to http://pmid.us/18789672 . Let us know what side effects you see with this protocol. After a few weeks it wouldn't be crazy to check liver enzymes. Is he on any concurrent conventional therapy?

[ppp]

Thanks all for your comments. I'd still be grateful for some more information regarding the bioavailability of the LiCaps versus non-micronised powders.

I believe that what is known about it comes from a Sirtris patent and/or presentation, though I've lost track of the data. Perhaps someone else will have it. (maxwatt? Anthony?) I'm of the opinion that the AUC (Area Under the Curve of plasma concentration vs time) is more important than the Cmax (maximal concentration; peak of the curve). The Cmax is very transitory while the AUC represents total body exposure to the drug. Formulation of resveratrol tends to have a bigger effect on the Cmax than it does on AUC, so in making comparisons, try to keep in mind which parameter it is. My recollection is that Cmax improved by somewhat less than a factor of ten, and AUC was a fair amount less good than that. The formulation used in animal experiments is should be reported, but often is not.

Morning (on an empty stomach): EGCG (600 mg) + Quercetin (1.6 gm) + Bromelain, followed 15-20 mins later by 8 LiCaps (2 gm). Wait at least 30m minutes before food.

Daytime: Selenite (1 mg), D3 (10000 IU), Black seed oil, 2 x Optiberry 30 mg, 2 x ActivaMune (bioavailable DIM)

Night (on an empty stomach): EGCG (600 mg) + Quercetin (1.6 gm) + Bromelain, followed 15-20 mins later by 8 gm of LongVida (bioavailable curcumin).

It looks good. The resveratrol dose at ~40mg/kg should be within the pro-apoptotic range (at least for ischemic rat myocardium) according to http://pmid.us/18789672 . Let us know what side effects you see with this protocol. After a few weeks it wouldn't be crazy to check liver enzymes. Is he on any concurrent conventional therapy?

His tumour is chemo-resistant so he's off that completely now. Aside from what I've listed he also takes omega-3 oils and ganoderma lucidum tablets. The only conventional treament is one he just started: pegylated interferon-alpha2b. Liver enzymes will be tracked for that.

[ppp]

It looks good. The resveratrol dose at ~40mg/kg should be within the pro-apoptotic range (at least for ischemic rat myocardium) according to http://pmid.us/18789672 . Let us know what side effects you see with this protocol.

The in-vitro level that showed apoptosis in a range of osteosarcoma cell lines was 5uM, with a dose dependent effect. The effect was increased by the addition of l-asparginase. Not sure how to go from mg intake to uM...