Enhanced Bioavailability And Tissue Effects Of Steroids Dissolved In Dmso

haidut

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As discussed in another thread related to DHEA, subcutaneous administration of steroids is considered the golden standard for bioavailability and systemic effects. That same study showed that topical application of DHEA dissolved in popylene glycol is only 33% as bioavailable as through subcunateous injection.
Bioavailability, androgenicity, and estrogenicity of DHEA | Ray Peat Forum

The studies below (last one is a human study) show that steroids dissolved in DMSO have the same bioavailability as subcutaneously administered steroids, and on average, dissolving in DMSO improves bioavailability 3 - 10 fold. The effects is also systemic, so the steroids do reach all tissues and do not simply get excreted through second pass metabolism as some people on the forum have suggested. Availability of tissue fat apparently is irrelevant for tissue penetration of DMSO. So, it seems that DMSO is at least as good a steroid carrier as the tocopherol/oil combination and rivals the accepted gold standard of subcunatenous injection. Given my recent post about copper dissolved in DMSO as a treatment of ALS, it suggests that people having troubles absorbing ANY dietary substance may have much better results by dissolving it in DMSO and administering topically.

Dimethyl sulfoxide therapy in chronic skin ulcers. - PubMed - NCBI
"...This simple fact permitted them to realize the medicinal properties and therapeutic possibilities of this drug. Some 2 to 6 hours after application on the skin, it is distributed through the organism, and in the same period of time it reaches the highest blood levels...According to Professor Don C. Wood, of the School of Medicine of the University of Oregon, after DMSO has been applied, tissues either rich or poor in lipids contain the same amount of DMSO. The reason for this is unknown."


Pharmacologic and biochemical considerations of dimethyl sulfoxide. - PubMed - NCBI
"...Weismann and colleagues [117] have shown that lysosomes can be stabilized with cortisone against many types of damaging agents. When cortisone was dissolved in DMSO, the dilution of cortisone necessary to protect the lysosome was reduced from 1:10 to 1:1000. It was suggested that DMSO might provide a vehicle that makes steroids more readily available to target tissues, thus resulting in reduced inflammation as evidenced by the experimental models described above."

Percutaneous absorption of two steroids dissolved in dimethyl sulfoxide in the immature female rat. - PubMed - NCBI
"...The steroids were given to the animals either in an aqueous suspension s.c., or applied topically in DMSO. Vaginal and uterine weight increases resulting from estrogen stimulation, and thymus, spleen and adrenal involution resulting from the exogenous cortisone were comparable in animals subjected to the two routes of administration, with a few noted exceptions."

"...Because it has been demonstrated that 17-/3-estradiol will cross the cutaneous barrier in an ointment base, a group of animals were administered 0.4 pg of 17-P-estradiol in 0.5 ml of sesame oil, utilizing the same technique employed for the estrogen-DMSO-treated animals. Average vaginal weight response in these animals were comparable to those observed in animals administered 0.4 pg estradiol s.c. or 0.5 p estradiol topically in DMSO (FIGURE 1). It was necessary, however, to use dosages in oil. 2.5 greater than those administered in DMSO to obtain uterine weight increases of the same order."

"...Average body weight gains (+ 2.5 gm, +2.8 gm) and average adrenal weight (23.1 mg, 25.2 mg) were not significantly different for the two dosages employed in oil and are comparable to those obtained from animals treated S.C. with 1 mg of cortisone. In none of the parameters measured, except for body weight changes, did the topical ap- plication in oil approximate the figures obtained from animals treated in the same fashion with the steroid in DMSO."

"...At these concentrations, the use of undiluted DMSO is feasible and it has been demonstrated that undiluted DMSO is the most effective concentration for moving steroids across the skin barrier."

"...A comparison of the organ weight response to the topically applied steroids in the two solvents used in the experiments reported here, DMSO and sesame oil, indicates that DMSO most closely mimics the results obtained by S.C. administration of these compounds. It can be concluded that DMSO effectively transports 17-0-estradiol and cortisone acetate across the skin barrier in immature female rats and does not markedly reduce the effects of these two steroids on organ response when examined gravimetrically, if a minimal vol- ume of undiluted DMSO is employed."

The effect of DMSO on percutaneous penetration of hydrocortisone and testosterone in man. - PubMed - NCBI
"...Radio-labeled 4C hydrocortisone and testosterone were applied to human skin in acetone alone and in DMSO. Penetration quantitated by assaying the 14C appearing in urine for five days. Without DMSO, 12 times as much testosterone penetrated as hydrocortisone. DMSO increased the penetration of both steroids three-and-one-half times. The significance of these findings is discussed."
 
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Koveras

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"
DMSO dissolved in popylene glycol

Believe you meant DHEA

On a related note I recently suffered from a bad case of contact dermatitis from using Pansterone and Tyromax. I had used the products without issues for several days (aside from an occasional and transient stinging/burning sensation). However on the 3rd or 4th day the redness and burning sensation maintained and progressed into some severe itching and many small vesicles formed around the border of the area of application. The issue was unaffected by a combination of cyproheptadine and benadryl, and only started to be relieved after several days when prescribed a glucocorticoid cream by my doctor.

It seems like this is likely a property / a risk of the DMSO itself :

The spectrum of inflammatory cell response to dimethyl sulfoxide. - PubMed - NCBI

However, my wife continues to use the Tyromax product with no issue. Did you have any insights as to why this issue may have presented itself, alternative strategies to deal with the issue if it ever occurs again, or strategies to prevent it (assuming there are no separate issues with the product)?

I am hesitant to retest the product at this time.
 

haidut

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"


Believe you meant DHEA

On a related note I recently suffered from a bad case of contact dermatitis from using Pansterone and Tyromax. I had used the products without issues for several days (aside from an occasional and transient stinging/burning sensation). However on the 3rd or 4th day the redness and burning sensation maintained and progressed into some severe itching and many small vesicles formed around the border of the area of application. The issue was unaffected by a combination of cyproheptadine and benadryl, and only started to be relieved after several days when prescribed a glucocorticoid cream by my doctor.

It seems like this is likely a property / a risk of the DMSO itself :

The spectrum of inflammatory cell response to dimethyl sulfoxide. - PubMed - NCBI

However, my wife continues to use the Tyromax product with no issue. Did you have any insights as to why this issue may have presented itself, alternative strategies to deal with the issue if it ever occurs again, or strategies to prevent it (assuming there are no separate issues with the product)?

I am hesitant to retest the product at this time.

Yes, it is DHEA. Thanks for catching, I corrected it.
I don't know why some people seem to be more sensitive to topical DMSO-based products. However, it seems that spreading over a larger skin area and/or diluting the drops with some extra ethanol like vodka, or rubbing alcohol resolves the irritation issue. I would like to reduce the concentration of DMSO but all the studies I have seen so far say 90% DMSO concentration is best for steroid absorption and no less than 50% is needed unless you have another carrier like propylene glycol, which is toxic. I am still experimenting with other carriers, so this is definitely not the final formula as I'd like to remove the skin irritation risk altogether and that seems to happen when DMSO concentrations drop below 60%.
 
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Wilfrid

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And what about using " Azone " instead of the DMSO?
It compares favorably to it minus the skin irritation issue.
 

haidut

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And what about using " Azone " instead of the DMSO?
It compares favorably to it minus the skin irritation issue.

That is certainly an option to test but I don't know of a reliable Azone supplier in US that can sell USP-grade material.
 

Wilfrid

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I just emailed Dr Howard Maibach and asked about a supplier of the highest grade of Azone in the US.
I will post the answer, if I get one. :)
What do you think of urea as a penetration enhancer?
 

jyb

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Well, progest-E seems to use vitamin E as the carrier and seems to absorb quickly topically (on the lips). Maybe this could work with other steroids as well?
 

haidut

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I just emailed Dr Howard Maibach and asked about a supplier of the highest grade of Azone in the US.
I will post the answer, if I get one. :)
What do you think of urea as a penetration enhancer?

Could work in principle, as would taurine and glycine. The latter have been found to increase topical absorption of many vitamins and even steroids. But I am more interested in things that can match DMSO and so far only Azone looks like it is up to the task.
 

Wagner83

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However, it seems that spreading over a larger skin area and/or diluting the drops with some extra ethanol like vodka, or rubbing alcohol resolves the irritation issue. I would like to reduce the concentration of DMSO but all the studies I have seen so far say 90% DMSO concentration is best for steroid absorption and no less than 75% is needed unless you have another carrier like propylene glycol, which is toxic. I am still experimenting with other carriers, so this is definitely not the final formula as I'd like to remove the skin irritation risk altogether and that seems to happen when DMSO concentrations drop below 30%.

Two studies I have no access to:

SKIN PENETRATING PROPERTY OF DRUGS DISSOLVED IN DIMETHYLSULFOXIDE (DMSO) AND OTHER VEHICLES. - PubMed - NCBI
INFLUENCE OF DIMETHYLSULFOXIDE (DMSO) ON HUMAN PERCUTANEOUS ABSORPTION. - PubMed - NCBI

Percutaneous Penetration Enhancers

In the last link they say 60% + of dmso is needeed for absorption enhancement, from what I remember higher concentration gives better absorption.
 
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haidut

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Two studies I have no access to:

SKIN PENETRATING PROPERTY OF DRUGS DISSOLVED IN DIMETHYLSULFOXIDE (DMSO) AND OTHER VEHICLES. - PubMed - NCBI
INFLUENCE OF DIMETHYLSULFOXIDE (DMSO) ON HUMAN PERCUTANEOUS ABSORPTION. - PubMed - NCBI

Percutaneous Penetration Enhancers

In the last link they say 60% + of dmso is needeed for absorption enhancement, from what I remember higher concentration gives better absorption.

As I mentioned in our PM discussion, actually these studies found even 5% DMSO concentration to be effective (second study). We will also be using another solvent mixed with the DMSO, so DMSO will carry part of the chemical and the other solvent the rest. As you can see from that second study, even water was effective as a solvent when using something topically.
"...The tails of conscious mice were immersed in 5 percent solutions of various psychoactive drugs dissolved in dimethylsulfoaide (DMSO), and the resulting behavioral effects were observed . In most instances, the drugs exerted their usual pharmacological effects, indicating penetration of the drugs through the skin. Several other solvents were also examined for their "drug-carrying" ability . All solvents, including water, permitted penetration of drugs across the skin barrier, although their rates of penetration were different."

That last link from Google, actually says anything above 50% DMSO when using dissolved chemicals worked well.
"...Using tape stripping to assess penetration into the SC in vivo, it was found that the fluorescent dye tetrachlorosalicylanilide could penetrate to the very base of the horny layer in only a few minutes when the DMSO concentration was 60% or above. The same endpoint took 2h with an ethylene glycol monomethylether vehicle and 6 days with a petrolatum vehicle. A similar effect was noted with the fluorescent antibiotic demethylchlortetracycline. Penetration to the base of the horny layer took substantially less time when the vehicle was 50% DMSO or higher. From water alone, the time for complete penetration was > 3h. At 50, 70 and 90% DMSO the time was reduced to 120, 55, and 20 min respectively.
 

Wagner83

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As I mentioned in our PM discussion, actually these studies found even 5% DMSO concentration to be effective (second study). We will also be using another solvent mixed with the DMSO, so DMSO will carry part of the chemical and the other solvent the rest. As you can see from that second study, even water was effective as a solvent when using something topically.
"...The tails of conscious mice were immersed in 5 percent solutions of various psychoactive drugs dissolved in dimethylsulfoaide (DMSO), and the resulting behavioral effects were observed . In most instances, the drugs exerted their usual pharmacological effects, indicating penetration of the drugs through the skin. Several other solvents were also examined for their "drug-carrying" ability . All solvents, including water, permitted penetration of drugs across the skin barrier, although their rates of penetration were different."

That last link from Google, actually says anything above 50% DMSO when using dissolved chemicals worked well.
"...Using tape stripping to assess penetration into the SC in vivo, it was found that the fluorescent dye tetrachlorosalicylanilide could penetrate to the very base of the horny layer in only a few minutes when the DMSO concentration was 60% or above. The same endpoint took 2h with an ethylene glycol monomethylether vehicle and 6 days with a petrolatum vehicle. A similar effect was noted with the fluorescent antibiotic demethylchlortetracycline. Penetration to the base of the horny layer took substantially less time when the vehicle was 50% DMSO or higher. From water alone, the time for complete penetration was > 3h. At 50, 70 and 90% DMSO the time was reduced to 120, 55, and 20 min respectively.

Ok however those were immersed in the drug, I would expect a 5% dmso solution to work a lot lot less than even 40-50%. Even with water the drug penetrated , Id like to see whether dmso at 5% beats all the suggested alternatives and if so by what margin.

From the same google book:
"Although the precise mechanism of action of dmso remains a matter of speculation, key elements underlying its enhancer properties must be taken into account:
1. it acts quickly , e.g. , a drug reservoir can be established in the SC in 30 mn or less (10) , and 2. high concentrations (>60% in water) are essential (11,12,17,20,23)."

From what I undersand they are saying dmso still enhanced how quick the drug was absorbed compared to other alternatives in the horny layer, but does something penetrating the horny layer means it is fully absorbed in the blood?
It sounds that dmso still took a lot of time to carry the drug inside the skin, doesn't it mean we should avoid any contact with potentially harmful stuff for respectively 120,55 and 20 mn depending on the concentration of dmso?
 

haidut

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Ok however those were immersed in the drug, I would expect a 5% dmso solution to work a lot lot less than even 40-50%. Even with water the drug penetrated , Id like to see whether dmso at 5% beats all the suggested alternatives and if so by what margin.

From the same google book:
"Although the precise mechanism of action of dmso remains a matter of speculation, key elements underlying its enhancer properties must be taken into account:
1. it acts quickly , e.g. , a drug reservoir can be established in the SC in 30 mn or less (10) , and 2. high concentrations (>60% in water) are essential (11,12,17,20,23)."

From what I undersand they are saying dmso still enhanced how quick the drug was absorbed compared to other alternatives in the horny layer, but does something penetrating the horny layer means it is fully absorbed in the blood?
It sounds that dmso still took a lot of time to carry the drug inside the skin, doesn't it mean we should avoid any contact with potentially harmful stuff for respectively 120,55 and 20 mn depending on the concentration of dmso?

The 60% cutoff was when DMSO was mixed with water. Water has inferior carrier capability compared to something like ethanol or PEG (when trying to absorb fat-loving chemicals like steroids), so mixing DMSO with some other good solvent will not have the same cutoff of 60%. That is why the 5% worked. Immersing is not much different when putting drops on skin and spreading them. As far as waiting - in some responses to people asking about it, I did advise an ideal waiting time of about 30min before washing the skin area, but absorption starts immediately. I don't think the issue with getting substances through the skin is as problematic as some Internet blogs make it out to be. The Dalton limit applies for carrying chemicals through the skin, so most pathogens will probably not be at risk for getting inside. Also, there is ethanol in our supplements and one of the purposes it serves is to disinfect the area. DMSO itself can also be a disinfectant / sterilizing agent. Ethanol is also a solvent. If it was as dangerous to rub this solvent on the skin it would not be used as skin clearing agent before surgery, injections, etc. So, when using supplements dissolved in DMSO/ethanol, you are using a powerful sterilizing agent, which makes it probably less risky then applying something dissolved in tocopherol and oil (which are a lot weaker as sterilizing agents).
http://www.plantphysiol.org/content/45/4/537.full.pdf
"...First, the high solubility of these compounds in DMSO' has made it possible to test the less active materials, or those which are only slightly water-soluble, through a wide range of concentrations; secondly, full strength DMSO stock solutions act as sterilizing agents."
 

Makaveli

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Could DMSO be causing a certain taste in my mouth? I've noticed this taste whenever topically applying androsterone, pansterone etc... My gf can smell it on me but she doesn't mind it. She may even like it.
 

BastiFuntasty

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Could DMSO be causing a certain taste in my mouth? I've noticed this taste whenever topically applying androsterone, pansterone etc... My gf can smell it on me but she doesn't mind it. She may even like it.
Indeed some people get a garlic like smell in their mouth, but it differs from person to person.
 

Wagner83

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If you are applying androsterone then it may be what your girlfriend smells, I have not noticed any garlic smell from the dmso haidut uses currently, your mileage may vary.
 

Wagner83

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The Permeability Enhancing Mechanism of DMSO in Ceramide Bilayers Simulated by Molecular Dynamics
At the molecular level, the DMSO molecules tend to accumulate at the interface, where they displace the water molecules. This is not surprising given that the DMSO molecule is amphiphilic. At high concentrations, the DMSO molecules integrate into the headgroup region, becoming involved in hydrogen bonding with the ceramide headgroups at the expense of the ceramide-ceramide hydrogen bonds. This disruption of the ceramide-ceramide hydrogen bonds enables the DMSO molecules to penetrate a little deeper and to effectively act as spacers. The lateral expansion of the bilayer destabilizes the lipid-tail packing, which results in the phase transition to the liquid crystalline phase. The resulting liquid-crystalline phase is characterized by a reduced bilayer thickness, a high degree of disorder of the lipid tails, and a low area compressibility modulus.
[....]
In conclusion, we have carried out simulations of ceramide 2 bilayers in the gel phase with different concentrations of DMSO (0.0−0.6 mol fraction). DMSO at high concentrations (≥0.4 mol fraction) induces the gel-phase structure to undergo a transition to the liquid-crystalline phase. The origin of this transition appears to be the accumulation of DMSO molecules at the headgroup region, where the molecules integrate, making hydrogen bonds with the lipid headgroups at the expense of the ceramide-ceramide hydrogen bonding. The weakening of the lateral forces and the ensuing expansion in the lipid area causes destabilization of the lipid tail packing resulting in the phase transition to the liquid-crystalline structure.

Effects of Dimethyl Sulfoxide in Cholesterol-Containing Lipid Membranes: A Comparative Study of Experiments In Silico and with Cells

Abstract
Dimethyl sulfoxide (DMSO) has been known to enhance cell membrane permeability of drugs or DNA. Molecular dynamics (MD) simulations with single-component lipid bilayers predicted the existence of three regimes of action of DMSO: membrane loosening, pore formation and bilayer collapse. We show here that these modes of action are also reproduced in the presence of cholesterol in the bilayer, and we provide a description at the atomic detail of the DMSO-mediated process of pore formation in cholesterol-containing lipid membranes. We also successfully explore the applicability of DMSO to promote plasma membrane permeability to water, calcium ions (Ca2+) and Yo-Pro-1 iodide (Yo-Pro-1) in living cell membranes. The experimental results on cells in culture can be easily explained according to the three expected regimes: in the presence of low doses of DMSO, the membrane of the cells exhibits undulations but no permeability increase can be detected, while at intermediate DMSO concentrations cells are permeabilized to water and calcium but not to larger molecules as Yo-Pro-1. These two behaviors can be associated to the MD-predicted consequences of the effects of the DMSO at low and intermediate DMSO concentrations. At larger DMSO concentrations, permeabilization is larger, as even Yo-Pro-1 can enter the cells as predicted by the DMSO-induced membrane-destructuring effects described in the MD simulations.

Protein precipitation and denaturation by dimethyl sulfoxide

Abstract
Organic solvents, including dimethyl sulfoxide (DMSO), have been used to precipitate, crystallize and denature proteins. We have studied here the interactions of DMSO with proteins by differential refractometry and amino acid solubility measurements. The proteins used, i.e., ribonuclease, lysozyme, β-lactoglobulin and chymotrypsinogen, all showed negative preferential DMSO binding, or preferential hydration, at low DMSO concentrations, where they are in the native state. As the DMSO concentration was increased, the preferential interaction changed from preferential hydration to preferential DMSO binding, except for ribonuclease. The preferential DMSO binding correlated with structural changes and unfolding of these proteins observed at higher DMSO concentrations. Amino acid solubility measurements showed that the interactions between glycine and DMSO are highly unfavorable, while the interactions of DMSO with aromatic and hydrophobic side chains are favorable. The observed preferential hydration of the native protein may be explained from a combination of the excluded volume effects of DMSO and the unfavorable interaction of DMSO with a polar surface, as manifested by the unfavorable interactions of DMSO with the polar uncharged glycine molecule. Such an unfavorable interaction of DMSO with the native protein correlates with the enhanced self-association and precipitation of proteins by DMSO. Conversely, the observed conformational changes at higher DMSO concentration are due to increased binding of DMSO to hydrophobic and aromatic side chains, which had been newly exposed on protein unfolding.
Maybe this one is worthless but I'll have a go anyway:
The methyl groups of DMSO are electron-donating, whereas that of methanol is electron-withdrawing, both making positive contributions. The findings reveal non-negligible effects of secondary alkyl groups in hydrogen bonding interaction and may shed light on the understanding of other more complicated hydrogen-bonded systems in chemical and biological systems.

Given that dmso also enchances steroids uptake into the cells, do these bits of information suggest we should be cautious about its effects on the cells (e.g. in testicles if applied directly on/close to the scrotum)?
 
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haidut

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The Permeability Enhancing Mechanism of DMSO in Ceramide Bilayers Simulated by Molecular Dynamics


Effects of Dimethyl Sulfoxide in Cholesterol-Containing Lipid Membranes: A Comparative Study of Experiments In Silico and with Cells



Protein precipitation and denaturation by dimethyl sulfoxide


Maybe this one is worthless but I'll have a go anyway:


Given that dmso also enchances steroids uptake into the cells, do these bits of information suggest we should be cautious about its effects on the cells (e.g. in testicles if applied directly on/close to the scrotum)?

Thanks for the links.
I think we should always be careful, even with vitamins applied to the scrotum. If you look at the thread on vitamin A and testosterone there is discussion about that too. Higher doses vitamin A can suppress T synthesis.
The DMSO concentrations mentioned in the studies you provided is quite large and not achievable with our supplement. One of the studies mentions 0.4M, which is 400mM, and that is a huge concentration, impossible to achieve in humans even with the multigram doses approved by the FDA. The other one found that DMSO concentrations higher than 40mol% had negative effects while lower concentrations were without effects. To achieve this 40mol% you'd have to suspend your scrotum in a glass of DMSO and let it soak for a few minutes. Not something (hopefully) people often do and definitely not something that can be achieved with a few drops of the DMSO in most supplements sold online (including ours).
Finally, I think we should ask Peat about the electron-donating and withdrawing properties of DMSO. He mentioned a few times that DMSO is a strong oxidizing agent, which means it should be electron-withdrawing. One of the studies said DMOS is electron-donating, so I would like to hear what Peat thinks about that.
 

Wagner83

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Cool thanks for the reply.

I'm interested in the properties of the dmso on the cells themselves (since even inside the body it seems to potently help with the effects of steroids on cells), so from what you are saying apart from the bit of skin that is exposed to the dmso (my guess, but I have gotten some pretty bad looking rash/irritation on the skin), concentrations should be low enough to not cause problems. Am I wrong if I say Ray does not believe in the idea of a lipid membrane around cells? Any thoughts on how to reconcile this idea with the studies I posted?

Maybe the electron-withdrawing properties are in fact very interesting and could help explain how dmso work on the cells within the body. I won't email Ray though as so far I've been ignored a few times. If someone in contact with him can be bothered he's welcome to it.
 
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haidut

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Cool thanks for the reply.

I'm interested in the properties of the dmso on the cells themselves (since even inside the body it seems to potently help with the effects of steroids on cells), so from what you are saying apart from the bit of skin that is exposed to the dmso (my guess, but I have gotten some pretty bad looking rash/irritation on the skin), concentrations should be low enough to not cause problems. Am I wrong if I say Ray does not believe in the idea of a lipid membrane around cells? Any thoughts on how to reconcile this idea with the studies I posted?

Maybe the electron-withdrawing properties are in fact very interesting and could help explain how dmso work on the cells within the body. I won't email Ray though as so far I've been ignored a few times. If someone in contact with him can be bothered he's welcome to it.

I think somebody asked him about the effects of DMSO on the membrane and his response was similar to one of the studies you posted - i.e. changes the cell state from a gel to a liquid-crystalline, which is supposed to be the more stable phase. Don't know much about that, except that this is the reason DMSO is used on cryopreservation - i.e. if the cell stays in the gel phase it will rupture when frozen.
 

Wagner83

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I think somebody asked him about the effects of DMSO on the membrane and his response was similar to one of the studies you posted - i.e. changes the cell state from a gel to a liquid-crystalline, which is supposed to be the more stable phase. Don't know much about that, except that this is the reason DMSO is used on cryopreservation - i.e. if the cell stays in the gel phase it will rupture when frozen.
Ok.
By the way how do you convert in vitro doses to in vivo?
From the little I've read it seems very tricky if accurate at all. Do you just use total blood volume ?
I saw an interesting study on how to convert doses in animal studies to humans but that's about it Dose translation from animal to human studies revisited. - PubMed - NCBI .

I could be wrong but it makes sense that depending on where dmso gets absorbed the cells will be exposed to different concentrations , so that if applied on testicles dmso will have a higher concentration in those cells than in the stomach. Maybe the dilution happens quick enough to make the issue irrelevant (except for the skin which does seem to suffer).
 
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