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Failed Flaxseed and Bad News Brownies

Well, it’s been a tough month for herbs since my last monthly soiree here at SBM.

Just last week at the American Society for Clinical Oncology (ASCO) meeting, a group out of the Mayo Clinic presented data from a study showing that a well-characterized flaxseed extract was ineffective against hot flashes in postmenopausal women. But as Steve Novella noted here earlier this week, negative clinical trials data on supplements rarely influence the behavior of those who continue to advocate for their herbal use.

Flaxseed, known to contain phytoestrogen compounds such as secoisolariciresinol diglucoside (SDG) and enterolactone, has been purported to relieve hot flashes.

But I think the hypothesis was flawed in the first place: while these compounds bind the estrogen receptor, they have largely been shown to be estrogen receptor modulators that act in a negative manner. Work from the group of Dr. Lillian Thompson at the University of Toronto has repeatedly shown in an estrogen-dependent animal model of human breast cancer that flaxseed components act in a predominantly anti-estrogenic manner. One might suspect that hot flashes would be made worse by flaxseed, although this was not the case in the study presented as ASCO.

However, flaxseed is definitely a great source of fiber and may have preventive effects in prostate cancer, but not through an estrogenic mechanism. Instead, another flaxseed component, the omega-3 fatty acid alpha-linoleic acid (ALA), reduces the conversion of testosterone to its more active form, dihydrotestosterone. This work comes from a former colleague at Duke University, Wendy Demark-Wahnefried, now at the University of Texas-M.D. Anderson Cancer Center.

Bottom line: A good understanding of the basic science of herbal medicines is absolutely essential to good clinical trial design.

Don’t Bogart My Brownies

A story that’s more likely to have been seen by SBM readers is Lazy Cakes, a dietary supplement-laden brownie intended as a sleep-aid (here’s an example from NPR). The implied undercurrent of this product, of course, is the longstanding tradition of baking marijuana into brownies to – uh – get baked. The packaging itself evokes memories of the Grateful Dead, Phish, and Widespread Panic – musical groups closely associated with marijuana use who the reader will identify with depending on their age. Their tagline, “Relaxation Baked In,” isn’t even a veiled association with this traditional herbal practice.

Lazy Cakes have created an uproar in part because they contain a dietary supplement with potential of central nervous system activity, melatonin. This naturally-occurring hormone is synthesized in the pineal gland and appears to regulate our circadian rhythms. The reader may best recognize melatonin for prevention of jet lag. It is, in simple terms, a sedative and appears to be more potent in younger people. National poison control centers report several thousand calls regarding melatonin each year, with the majority of reports of sedation in children who’ve gotten hold of a parents supplement. Here’s one example from the Texas Department of State Health Services.

Lazy Cakes might also be riding on the well-known Philadelphia-area delicacy, Tastykake. The fact that I have included Tastykake in a post about Lazy Cakes is most certainly not pleasing to this East Coast institution but I have yet to find anything in the Philadelphia press about this issue. (By the way, these wonders of the food world fueled my childhood development as well as my scientific training at the school known previously as the Philadelphia College of Pharmacy and Science.)

The concern with Lazy Cakes seems to be that each brownie contains 7.8 mg of melatonin, well above the generally recommended sleeptime dose of 1 to 3 mg. While there have been no controlled trials of Lazy Cakes, anecdotal reports suggest that the brownies do indeed have physiological action. From the NPR story:

“There is an effect with Lazy Cakes, but I wouldn’t say it’s comparable to marijuana at all,” says Niki D’Andrea, who bought one while at a shop that sells drug paraphernalia.

D’Andrea’s not shy about having tried both; it’s part of her job writing about subculture for the Phoenix New Times. She didn’t get high from the Lazy Cake, but she was shocked at how sleepy it made her.

“I really did go to bed for about, I think 10 to 12 hours after I ate that first Lazy Cake, so well, maybe I should have started with half,” D’Andrea says.

Actually, half is the recommended serving size. As if anyone ever just eats half a brownie.

Less attention has been given to the other herbal components: valerian and passionflower extracts.

Valerian (Valeriana officinalis L.) has been investigated for sleep-inducing and anti-anxiety effects. In fact, some of the same researchers who presented the ASCO work above on flaxseed conducted a Phase III trial of valerian extract in cancer patients. Published earlier this year in the Journal of Supportive Oncology, the study revealed that this valerian root extract had no effect on overall measures of sleep efficacy, although some beneficial effects were observed on secondary measures such as fatigue.

However, we have no idea what valerian might do together with this rather high dose of melatonin. Come to think of it, I have no idea how the manufacturer made a valerian-containing brownie even remotely palatable. I have a 16-year-old bottle of valerian root that I use for classroom demonstrations and it still smells of rancid gym socks. But, then again, baking valerian extract is likely to release some of these volatiles.

Less is known about passionflower (Passiflora incarnata). Even a Cochrane review of passionflower for anxiety was unable to come to a solid conclusion due to the low number of studies.

Another issue not addressed in most MSM reports is that the actual content of components can vary wildly from amounts listed on dietary supplement labels. In most cases, the products contain less but this inconsistency is concerning with a product that contains a human hormone well-known to induce sleep.

The bottom line: don’t mess with Lazy Cakes. As with any sedative drug – whether a supplement, prescription or over-the-counter – there’s always a concern for additive or synergistic effects with alcohol.

But rest assured that the uproar over Lazy Cakes will further fuel sales. And given dietary supplement regulations in the United States, I really don’t see this product being banned – although the manufacturer has added additional warnings about sedation and intended use by adults.

That’s right – a product featuring a sleepy brownie that resembles Spongebob Squarepants is intended solely for adults.

Posted in: Cancer, Clinical Trials, Herbs & Supplements

Leave a Comment (49) ↓

49 thoughts on “Failed Flaxseed and Bad News Brownies

  1. passionlessDrone says:

    Hello friends –

    I have a 16-year-old bottle of valerian root that I use for classroom demonstrations and it still smells of rancid gym socks.

    That is exactly what I was thinking about when I read that there was valerian root in them!

    Haven’t tried lazy cakes yet, generally I don’t have time to be lazy, but it was the expected reaction to the relative explosion of X Hour Energy drinks with ‘no crash’. How many people out there are chasing a five hour energy with a lazy cake, I wonder?

    - pD

  2. Nescio says:

    Interesting, thanks. It wasn’t long ago I had a long on-line argument with some CAM proponents who swear that flaxseed and cottage cheese cures cancer, and everything else. I wish someone would do a good refutation of that particular idea – it’s called the Budwig method should anyone feel like it. I could find only limited information about it, apart from sites promoting it.

    Valerian is as appealing (and intoxicating) to cats as catnip, as I discovered years ago when my cats got into a bag of valerian. Valerian everywhere, two stoned cats slumped on the couch with eyes like saucers. I used to drink valerian tea as a sleeping aid, but I couldn’t say if it had any effect over placebo. I quite like the smell, my wife loathes it.

    Passionflower contains small amounts of harmine and harmaline, the MAO inhibiting hallucinogens that are present in ayahuasca, and are responsible for making the DMT in it orally active. Whether there is enough there to have a synergistic effect with the valerian and melatonin, who knows?

  3. Mark Crislip says:

    I didn’t realize that a peanut butter and jelly sandwich is also a sleep aid. I have one most days for lunch at noon and I’ll be damned that I am also really sleepy 10 to 12 hours later and ready for bed, just like Lazy Cakes.

  4. JPZ says:

    Not to go too far off topic, but flaxseed is a very effective in maintaining regularity. I was at a fatty acid conference several years ago, and one of the attendees provided some rather tasty cookies containing a significant amount of flaxseed. No “adverse events” or anything like that, but the efficacy was self-evident. I’ve occasionally wondered about flaxseed efficacy and side-effect profile compared to inulin or beans, etc.

  5. daedalus2u says:

    Anything with enough Valerian to have effects could well be a teratogen and could increase the incidence of autism and also neural tube defects. The active ingredient has similar effects and chemical structure to Valproic acid which is known to cause increased autism from exposure in utero.

  6. Here in Michigan we have Zingerman’s brownie, which don’t need to claim any medicinal benefits, cause they are just so damn good.

    Really good, particularly if you warm them up just a bit (sigh).

    But, I must add, I do remember on numerous occassions, feeling an incredible lassitude spreading over me when settling down to get some work after a hearty lunch followed by a Zingerman’s brownie.

    At my old workplace this was commonly known as “food coma”.

    And (aside from food allergy issues) I don’t believe anyone’s ever had to call poison control over a Zingerman brownie.

  7. Anthro says:

    @JPZ

    I’ve had similar “reactions” to flaxseed, even a small amount such as in bread. My spouse has no such problem. Individual tolerances for fiber is my guess. I get hideous gas from anything high fiber–dried apricots, beans, flaxseed, broccoli–he eats them all with impunity. I read once that some people lack an enzyme (or two) that helps break down fiber.

  8. kulkarniravi says:

    Dunno about this study, but flaxseeds floor tastes yummy when added to many preparations. I will continue to eat it.

  9. Harriet Hall says:

    @kulkarniravi,
    Do you have hot flashes? Are you eating flaxseed for food, or for some perceived health benefit?

  10. kulkarniravi says:

    Not likely to have hot flashes any time soon as I am male. Flaxseed is good food that has some benefits for the heart. Much better than eating white floor bread. I don’t have double blind peer reviewed clinical studies as a source, but I gotta eat something.

  11. aegimius says:

    Good info, although hot flashes were never an issue for me and I doubt will ever be an issue for me ;)

    This study was basically meaningless for me as a flaxseed consumer(but hopefully meaningful for a lot of other people), so I will continue to eat flaxseeds for the taste, the fiber, omega 3 content and possible prostate cancer protective effect.

  12. kulkarniravi says:

    I notice almost an unholy glee among the medical community about every “failed” supplement or food. People have been eating these foods for thousands of years and they will continue to do so. Not many eat isolated/concentrated active ingredients that purportedly benefit health. Perhaps that’s one reason why many of these trials fail in the first place?

    1. Actually, I am very disappointed whenever I see any of these dietary or herbal supplements fail. You may not know that my research is devoted to this field: examining natural sources for the activity of complex herbal mixtures or single drug compounds. I would argue that if there are herbal supplements that actually have the potential for benefit but are found negative in trials, the basic science underlying the clinical trial design might be flawed. For example, in most cases these trials don’t evaluate plasma concentrations of active constituents in the clinical trials subjects. This is normally the very first thing done in clinical trials of prescription drugs (i.e., to ensure that the dose given produces blood concentrations consistent with the physiological effect(s).)

  13. Harriet Hall says:

    @kulkarniravi,
    “Not many eat isolated/concentrated active ingredients that purportedly benefit health.”

    That’s pretty much our point: that these supplements/foods are fine as part of a healthy diet, but that they are seldom effective as medicines.

    No one is saying we should not eat flaxseed, only that it isn’t an effective remedy for hot flashes.

  14. BillyJoe says:

    “I notice almost an unholy glee among the medical community about every “failed” supplement or food. ”

    :D

  15. JPZ says:

    @Harriet

    The more I learn, the less I can draw that distinction between food and drug. To draw upon my previous example, there are prescription-only drugs (Amitiza) for constipation and there are those yummy flaxseed cookies I had. Same outcome, one is a drug and one is a food. I can invent ways to separate these two, but the line keeps getting blurrier the more I learn. I guess I am getting too old to admit I know everything! LOL

    IMHO, I think proven efficacy is the more important criterion, i.e. flaxseed probably doesn’t work for hot flashes.

  16. nybgrus says:

    @JPZ:

    I think that is the key here. Certain things are pretty obviously foods (like flaxseed). If you were to concentrate the contents so you could ingest the equivalent of many times what you could normally eat (say flaxseed capsules equivalent to 2 lbs of seed) then it is no longer a food. But what about just eating a flaxseed cookie? Still food as far as I am concerned, but the intent is what really matters. If you say it helps you with your bowel habitus – well, we can study that if needed. Same with hotflashes.

    So as Dr. Hall said, eat it if you like the taste and the nutrients (and apparently if you need some regalarity in your life). But not if you think it will help your hotflashes. At that point is crosses into drug-like claims, we can evaulate them, and then decide it isn’t helpful. In cases like this if you do anyways, I reckon there is no harm – unless you decide to eat flaxseed instead of some other proven intervention that you need (not that I can really think of something like that in this case – if you think you aren’t miserable with hot flashes, then you aren’t).

    But your comment also strikes at the heart of what we have all been saying here at SBM – there is no CAM dichotomy. It is very hard to distinguish food from drug sometimes and many, many drugs come from foods and other “natural” sources. There is nothing “alternative” about that. Science has been using and describing these things for ages. The only time “alternative” applies is when you don’t know what, if anything, it does and still go ahead and use it. Hence, “alternative medicine is just medicine that doesn’t work or hasn’t yet been proven to work. Once it is shown to work, it is just ‘medicine.’”

  17. JPZ says:

    @nybgrus

    I always enjoy reading your thoughtful commentary, but I feel I must respectfully disagree. The criteria can’t be “if it works.” If flaxseed and Amitiza both work for chronic constipation, then that does not make them both drugs. If the DASH diet and statins both work for heart disease prevention, then that does not make them both drugs. If lutein reduces the risk of certain forms of macular degeneration (AREDS II) and (wait for it) nothing else does, then eating spinach does not become a drug. This is my point, the line between food, supplement and drug can not be drawn on the basis of “if it works.” If it works, then a patient should use it. Even if rubbing a cat on your head turns out to get rid of migraines (don’t laungh until the microarray genomics are worked out :P ), the cat is not a drug. Its a kitteh.

  18. nybgrus says:

    @JPZ:

    Thanks for the kind words. And always feel free to disagree – that is how people learn.

    I do agree with you to an extent and certainly the line is very blurry, especially at such crossroads betwixt food and drug. However, I did not say that whether it works was the key definition for me – it was the intent.

    Carbon tetrachloride is not a “drug” it is an industrial solvent and poison. Yet kids are known to “huff” it to get high. Then it is a drug. If you had an industrial accident and were exposed to it and had liver failure you would call that an accident. If you huffed it to get high and got liver failure that would be an effect of drug abuse.

    So you are correct – eating spinach is not a drug. However, eating spinach specifically to prevent macular degeneration is using a drug. If the spinach eaten in normal amounts cannot have this effect and you must eat a bag a day every day, I would say that is downright and clearcut using it as a drug (you are trying to get enough of whatever active ingredient(s) are in it to effect the result, same as if you took a concentrated pill form).

    But what if the regular amount an average (or even avid) spinach eater ingests was enough to cause the effect? How would one class it then? I would have to fall back on intent. Eating spinach because you like the taste is food. Eating it because you want to prevent macular degeneration is a drug. Combining both simply means that it is both at the same time – and I am OK with that because as I said, the line is blurry and there are times when that will happen.

    However, science can test such a specific claim – a drug claim. That is why I can say to you “Don’t eat spinach because it does nothing for macular degeneration” (assuming the science said so, of course) but I can still say, “but do eat spinach as part of a healthy diet.”

    I would say your cat analogy fails because that is an external intervention, not an ingestion of a drug. Surgery is not a drug – but it can have profound effects. So can massage, and it is also not a drug. So yes, kitteh will always be kitteh, unless you decide to cook and eat him, or grind parts of him into powder and eat him (tiger penis as an aphrodisiac anyone?).

    I get that it is a fuzzy area (haha, no pun intended) but from what I have learned, the only meaningful way to define things like “drug,” “poison,” or “food” is by looking at intent first and mechanism of action second. Anything other definition leads to paradoxes and problems.

    At least, that is my opinion.

  19. Chris says:

    Okay, this is how in reality milled flax seed is used. This is not a pill, but a flour like substance ground from the seed.

    I take your basic blueberry muffin recipe for a dozen regular sized muffin. Then I triple the amounts because I have two “Texas” sized muffin tins. They each consist of six muffins holes that are triple the size of a “regular” muffin. Though instead of baking them at 425 degrees F for 25 minutes, you need to bake the larger muffins at 350 degrees F for 50 minutes, turning them at the halfway point for even baking.

    But then I only use one egg instead of three eggs, plus I use only one quarter a cup of oil instead of three quarters of a cup. What I do is put in a cup of homemade applesauce (from my apples, no sugar added), and half a cup of milled flax seed.

    Between the applesauce and milled flax seed the lack of oil and egg is not missed. Plus there is not annoying greasiness of the commercial muffins. The oil and egg have been replaced with fiber, which could only help JPZ’s issues.

    Last month I planted some “Catalina” baby leaf spinach, and it is going nuts. I will be plucking the outer leaves for some quicky stir fry soon. I also planted a salad mix of lettuces from a local nursery, and after plucking the other leaves for a second time the stuff is still growing strong. Even with sluggy competition. So there are easy ways to get good fiber if you are willing to till a small garden!

    And you get good protein if you don’t mind slugs. Though I did put the lettuce leaves into a large bowl which I filled with water. That seemed to drown the teeny tiny slugs as I picked the lettuce leaves out into a sink of water, then back into the bowl with fresh water (triple washed, of course) and then the salad spinner.

    I usually don’t mind the little black aphids in my artichokes. They are tiny and are perfectly harmless after I steam them.

    kulkarniravi, what grows in your garden?

  20. @Chris, does the milled flax seed retain some oil, is that why you can cut back on the oil so much? Or is dryness caused by cutting back the oil completely elevated by the applesauce?

    My MIL often uses the replace oil with apple sauce trick, but her muffins are often rather dry. I wonder if milled flax seed substitute would rectify the dryness.

  21. Chris says:

    Yes, the milled flax seed retains some oil. Though I suspect your MIL is not using enough applesauce and has totally skipped the oil. It also helps to really load up the muffins with blueberries.

  22. JPZ says:

    @nybgrus

    I find myself guilty of what has occasionally been done to me here – putting words into your mouth to make my point. My bad. The US FDA uses the exact same definition to distinguish between drugs and foods – intended use. I am uncomfortable with that definition because of the blurring between the two (as you mentioned).

    It is semantics whether I consume two servings of oily fish a week as part of a healthy diet or to get enough omega-3s to prevent a second heart attack (none of these are personal examples BTW). Those two servings are many times the dietary intake in the US but only a fraction of the dietary intake in say Norway. So, at what point are we increasing our omega-3 intake to drug efficacy levels for the intent of disease treatment? The whole concept of a healthy diet to prevent heart disease and cancer, etc. treats food as a drug by intent. The whole concept of a line between the two is starting to remind me of last week’s chalk drawings on the playground.

    I am still trying to figure out the answers for myself. If we allow drug claims for nutritional products, then we need safety profiles for physicians to monitor side effects and interactions, right? Extend the logic, and we have to ask whether putting statins in bottled water is OK. The lines are blurred right now, but I am not quite sure where to start drawing new ones.

    @Chris

    LOL “issues” Nope, I just didn’t realize how powerful a drug those flaxseed cookies were. Oh wait, “intended use” – junk food.

  23. nybgrus says:

    @JPZ:

    I find myself guilty of what has occasionally been done to me here – putting words into your mouth to make my point. My bad

    It’s ok. I know in general your intent is good and that is what matters to me ;-)

    On a serious point, however, I do agree with you that it becomes rather blurred. Of course, intellectual honesty is the best answer there, but we both know that is a precious commodity in short supply. However that is why I looked at intent first and then mechanism. I should have also included effect after that.

    For example:

    If a common food X is eaten normally with no other intended uses then we are done.

    If common food Y is eaten normally with no other intended uses, but for some reason someone suspects it has a deleterious effect, science evaluates it and discovers this to be true, we can then recommend Y no longer be eaten.

    Now lets say someone suspects food X is actually quite healthy and they do some science on it. They discover it helps condition A.

    If normal quantities of X can affect A with no noticeable side effects, then we can recommend it as a “healthy diet” in general and eating it specifically for A as a “drug.”

    Anything concentrated and/or put into pill form = drug. Period.

    Those to me are reasonably clear cut when just a smidge of intellectual honesty is applied. But you raise a very good point:

    If we allow drug claims for nutritional products, then we need safety profiles for physicians to monitor side effects and interactions, right?

    You are absolutely right. And this is where kulkarniravi’s ideas apply. Diet is an important factor in health and different diets can interact to differing degrees with drugs we give. We know a lot of that already – drinking grapefruit juice potentiates coffee and warfarin, eating an orange improves absorption of iron (supplement or liver form), etc. I think the problem we are having in this discussion is that the effect size for most food is rather small, the biochemistry is rather complex, and everyone is different. I drink a cup of prune juice and I’m in the bathroom 60 minutes later. My girlfriend can drink it and have no effect. Ultimately, having “perfect” knowledge of all foods and genomes and interactions will solve all these questions, but in the meantime we have to work with what we’ve got. We must assume that the effect size of a food is pretty small if existent at all (since most are, sorry kulkarniravi) and that they cannot cure, treat, or ameliorate disease. When something comes up that may have an interesting effect that is where science can come in. I think of it all as pharmacognosy, which is notoriously low-yield. If the science shows it has no effect (like flaxseed for hot flashes) then we can say that and move on. But if it does have an effect, we should strive to quantify it and determine what specifically is causing the effect (just as they are doing for turmeric and Alzheimers). In the meantime, we classify it by intent. When I cook with turmeric (I just did last night, for example) that is food, since my intent has nothing to do with Alzheimer’s. If I made it a point to cook with it very regularly for that effect then I am using it as a drug to hedge my bets.

    Does that really make any difference at the moment? No. Telling my doctor “I eat turmeric occasionally” vs “I eat turmeric pretty regularly because I want to stave off Alzheimer’s” is functionally the same statement. It may stay that way forever. But, my understanding is that it is suspected that the turmeric may supress the deposition of beta-amyloid and thus have its anti-Alzheimer effects. What if science discovers that to be a true mechanism but it does it by increasing TTR-amyloid (which binds beta-amyloid)? TTR-amyloid can deposit in the heart, amongst other places. So now your patient who has heart failure tells you that (s)he is eating heaps of turmeric specifically to prevent Alzheimer’s. You would then recommend (s)he discontinue this because of the risk of heart damage (all the science I described above is correct – only the precise link and mechanism has not been shown to be correct yet, but it could be in theory). But what if it is just used occasionally as food? Well, now we come to another part of practicing medicine. If the above science bore weight, and my patient was Indian (South Asian, not American) I would specifically ask them about their turmeric intake since I would expect it to be higher than other cultural groups. I would also recommend cutting down. If an average Caucasian American was my patient, I don’t think I would bother because their intake would be low enough not to matter.

    And that is why I think of intent as being of prime importance. In most cases right now, I agree that it makes no functional difference and only serves as a classification that in most cases currently doesn’t (and probably won’t ever) really be needed to actioned upon. But I can envision situations where it might be important and thus for homogeneity of classification for potential application I think it is important and that is my solution for it. Otherwise you can just get piles and piles of exemptions that could lead to significant interactions with no way of knowing or regulating it.

    But I think I see you hesitance – without intellectual honesty it could become a food Nazi situation with undue scrutiny, labeling, and regulation of simple as simple as Chris’s delicious sounding muffins.

  24. nybgrus says:

    *….and regulation of something as simple as….”

  25. BillyJoe says:

    micheleinmichigan,

    “I wonder if milled flax seed substitute would rectify the dryness.”

    Alternatively, could I suggest you try K-Y jelly. :)
    http://www.k-y.com/

  26. JPZ says:

    @BillyJoe

    Eww. You reminded me of “She Don’t Use Jelly” by the Flaming Lips. I hate that song.

    @nybgrus

    I respect your point of view and the reasoning you used to form it. I also know why the US FDA uses “intent” the way it does. I am just not comfortable with how the distinction plays games with good quality science, e.g. south pacific islanders eat 35 mg lutein a day on average, AMD efficacy (limited) is seen at 10 mg/d, people in the US eat something like 2 mg. What is normal? Now, go pull up a garden weed and tell me to eat it because it magically improves hearing – now THAT is abnormal. :)

    Heh, if our biggest disagreement is over “intent” versus “efficacy” – I’m good with that! ;)

  27. nybgrus says:

    @JPZ:

    I agree. This is one where reasonable people can disagree. And since we’ve gotten our disagreement down to those points, I’m quite content as well. A little intellectual honesty on a case-by-case basis will bridge with gap, I’m sure.

  28. hippiehunter says:

    Funny the cookies at Nimbin help me to sleep very effectively

  29. nybgrus says:

    I think the cookies from Nimbin contain a bit more than just melatonin ;-)

  30. sdavis2 says:

    Seems this blog is heavily biased toward showing failures and not successes. No wonder there aren’t more visitors.

    But I wouldn’t expect to see any from a site that claims green tea, milk thistle or turmeric don’t exhibit any significant clinical benefit and refers to the “Natural Medicines Comprehensive Database” (ha!) to figure out what they do. What a laugh! Time to study science again, guys.

  31. sdavis2 says:

    BTW, with regard to “antioxidant effects,” you might want to look up gamma-glutamylcysteine ligase, the rate-limiting precursor for glutathione which silymarin (milk thistle) significantly upregulates. Oops!

  32. Imadgeine says:

    Recipe tips on science based medicine. OK…
    Brownie debate a bit lost on us Europeans.
    Ground flaxseed added to morning cereal good for colon action – but I can confirm it does not cure hot flushes/flashes.
    Does the same science apply to soya then? That stuff about phytoestrogens always seemed puzzling.
    Wish someone would come up food that would cure hot flushes!
    But feeling very smug that I was always sceptical about black cohosh. Turns out this was a good call.

  33. nybgrus says:

    aw snap! sdavis2 just showed us! Better go back to the drawing board guys! We’ve been found out!

    thanks for the laugh

  34. sdavis2 says:

    @nybgrus, Seriously? This blog makes a claim to be about science and messes up like this? I’m merely providing balance here, which is much needed. Nothing against you, but when somebody says something that ain’t quite right, I’m going to correct them. I’m sure others will thank me.

  35. nybgrus says:

    yep. seriously. but thanks for laugh #2

  36. sdavis2 says:

    Eh, you’re a troll.

  37. nybgrus says:

    I’d suggest you read my posts before making such a claim.

    You however, are a different story. You come on here, make some snide remark with nothing at all to backup what you are saying, and expect anything but a snide comment in return?

    I hate to say this (well, not really) but you clearly don’t have a clue and making short little inflammatory comments of no substance make you… yup, a troll. So I laughed.

    But if you have something more substantive to say, and I happen to have time and am motivated enough, I’ll be glad to show you why you are wrong.

    But you aren’t off on a good foot so far, so I may choose to ignore.

  38. Scott says:

    Wish someone would come up food that would cure hot flushes!

    I’d suspect that any such “food” would have the same risks as HRT, because it would presumably be working by providing estrogen. Very hard to see how there would be any particular benefit to getting HRT in some form that can be (misleadingly, if it did that) labelled as “food.”

  39. Scott says:

    @ sdavis2:

    Just as a hint. If you want to claim that milk thistle really does have some real effect, you need to provide the PMID references demonstrating such. Simply stating it won’t get you anywhere in any setting where evidence is valued.

  40. sdavis2 says:

    MORE –

    GENERAL

    An Updated Systematic Review of the Pharmacology of Silymarin
    R. Sallera; J. Melzera; J. Reichlingb; R. Brignolic; R. Meierd
    Recent years have seen an explosion of scientific papers that deal with drugs from the fruits of milk thistle and its active substances silymarin (standardized mixture of flavonolignanes), thus justifying an updated systematic review. Methods: Electronic databases identified silymarin, silibinin, silicristin or milk thistle as descriptors in >700 papers (34% published in last 5 years; 92% dealt with animal pharmacological). Only papers adequately reporting on experimental conditions, dosing, variables tested and statistics were analysed. Results: Silymarin was found to modify specifically the functions related to various transporters and receptors located in the cell membranes; that is, organic anion uptake transporter peptides (OATP), ABC transporters (P-gp), bile salt export pump, as well as TNF-a-dependent and possibly selectin-dependent phenomena. In the cytoplasm, some antioxidant properties and the inhibition of the lipoxygenase pathway seem quite selective and could concur to the antitoxic effects. Some effects like the inhibition of inducible nitric-oxide synthase, of nuclear factor B, and reduction of collagen synthesis are indicative of DNA/RNAmediated effects. Several studies using ‘in vitro’ and ‘in vivo’ cancer models suggest a potential of silymarin in such diseases. Topical and systemic silymarin has skin protective properties against UV-induced damage in epidermis and causes an up-regulation of tumour-suppressor genes p53- and p21CIP1. There were no data on hepatic viral replication, viremia or spontaneous tumours in the data examined. Conclusions: Data presented here do not solve the question about the complex mechanism(s) of action of the medicinal herbal drug silymarin. Silymarin may be a natural multi-functional and multi-target drug.
    Copyright © 2007 S. Karger GmbH, Freiburg

    Integr Cancer Ther. 2007 Jun;6(2):146-57.
    Review of clinical trials evaluating safety and efficacy of milk thistle (Silybum marianum [L.] Gaertn.).
    Tamayo C, Diamond S.
    Research and Development at Flora Inc, Bethesda, MD 20817, USA. ctamayo2@comcast.net
    Milk thistle extracts have been used as traditional herbal remedies for almost 2000 years. The extracts are still widely used to protect the liver against toxins and to control chronic liver diseases. Recent experimental and clinical studies suggest that milk thistle extracts also have anticancer, antidiabetic, and cardioprotective effects. This article reviews clinical trials of milk thistle conducted in the past 5 years including pharmacokinetic and toxicity studies, herb-drug interactions, and other safety issues. Several trials have studied the effects of milk thistle for patients with liver diseases, cancer, hepatitis C, HIV, diabetes, and hypercholesterolemia. Promising results have been reported in the protective effect of milk thistle in certain types of cancer, and ongoing trials will provide more evidence about this effect. In addition, new established doses and improvement on the quality and standardization of this herb will provide the much-awaited evidence about the efficacy of milk thistle in the treatment of liver diseases. Milk thistle extracts are known to be safe and well tolerated, and toxic or adverse effects observed in the reviewed clinical trials seem to be minimal. The future of milk thistle research is promising, and high-quality randomized clinical trials on milk thistle versus placebo may be needed to further demonstrate the safety and efficacy of this herb.
    PMID: 17548793 [PubMed - indexed for MEDLINE]

    Integr Cancer Ther. 2007 Jun;6(2):104-9.
    Advances in the use of milk thistle (Silybum marianum).
    Post-White J, Ladas EJ, Kelly KM.
    University of Minnesota, Minneapolis, Minnesota 55403, USA. postw001@umn.edu

    Milk thistle (Silybum marianum) is an herbal supplement used to treat liver and biliary disorders. Silymarin, a mixture of flavanoid complexes, is the active component that protects liver and kidney cells from toxic effects of drugs, including chemotherapy. Although milk thistle has not significantly altered the course of chronic liver disease, it has reduced liver enzyme levels and demonstrated anti-inflammatory and T cell-modulating effects. There is strong preclinical evidence for silymarin’s hepatoprotective and anticarcinogenic effects, including inhibition of cancer cell growth in human prostate, skin, breast, and cervical cells. Milk thistle is considered safe and well-tolerated, with gastrointestinal upset, a mild laxative effect, and rare allergic reaction being the only adverse events reported when taken within the recommended dose range. More clinical trials of rigorous methodology, using standardized and well-defined products and dosages, are needed to evaluate the potential of silymarin against liver toxicity, chronic liver disease, and human cancers.
    PMID: 17548789 [PubMed - indexed for MEDLINE]

    LIVER

    Protective effects of silymarin, a milk thistle (Silybium marianum) derivative on ethanol-induced oxidative stress in liver
    SUBIR KUMAR DAS ; VASUDEVAN D. M. ;

    The production of reactive oxygen species (ROS) is considered to be a major factor in oxidative cell injury. The antioxidant activity or the inhibition of the generation of free radicals is important in providing protection against such hepatic damage. Silymarin, derived from the milk thistle plant, Silybium marianum, has been used in traditional medicine as a remedy for diseases of the liver and biliary tract. In the present study, the effect of hepatoprotective drug silymarin on body weight and biochemical parameters, particularly, antioxidant status of ethanol-exposed rats was studied and its efficacy was compared with the potent antioxidant, ascorbic acid as well as capacity of hepatic regeneration during abstention. Ethanol, at a dose of 1.6 g/kg body wt/day for 4 wks affected body weight in 16-18 week-old male albino rats (Wistar strain weighing 200-220 g). Thiobarbituric acid reactive substance (TEARS) level, superoxide dismutase (SOD), and glutathione-s-transferase (GST) activities were significantly increased, whereas GSH content, and catalase, glutathione reductase (GR) and GPx (glutathione peroxidase) activities significantly reduced, on ethanol exposure. These changes were reversed by silybin and ascorbic acid treatment. It was also observed that abstinence from ethanol might help in hepatic regeneration. Silybin showed a significant hepatoprotective activity, but activity was less than that of ascorbic acid. Furthermore, preventive measures were more effective than curative treatment.

    Indian journal of biochemistry & biophysics
    J Clin Gastroenterol. 2003 Oct;37(4):336-9.
    Silymarin retards the progression of alcohol-induced hepatic fibrosis in baboons.
    Lieber CS, Leo MA, Cao Q, Ren C, DeCarli LM.
    Section of Liver Disease & Nutrition, Bronx VA Medical Center & Mount Sinai School of Medicine, Bronx, New York 10468, USA. liebercs@aol.com
    GOAL/BACKGROUND: Hepatoprotective effects of silymarin in patients with alcoholic liver disease are controversial. For strict control, this was assessed in non-human primates. STUDY Twelve baboons were fed alcohol with or without silymarin for 3 years with a nutritionally adequate diet. RESULTS: Silymarin opposed the alcohol-induced oxidative stress (assessed by plasma 4-hydroxynonenal) and the rise in liver lipids and circulating ALT. Alcohol also increased hepatic collagen type I by 50% over the 3 years with a significant rise in mRNA for alpha1 (I) procollagen, both prevented by silymarin. There were corresponding morphologic changes: at 36 months, 2 of 6 animals fed alcohol had cirrhosis and 2 septal fibrosis, with perivenular fibrosis in 2, whereas with alcohol + silymarin, there was only 1 cirrhosis and 1 septal fibrosis, with perivenular fibrosis in 2, and virtually no lesions in the remaining 2. CONCLUSIONS: Silymarin retards the development of alcohol-induced hepatic fibrosis in baboons, consistent with several positive clinical trials. The negative outcome observed in other trials possibly reflects poor compliance resulting in irregular or low silymarin intake. Thus, in view of the innocuity of silymarin, it might be advisable in future clinical studies to insure the controlled administration of sufficient amounts of silymarin.
    PMID: 14506392 [PubMed - indexed for MEDLINE]

    Nutr Metab (Lond). 2008 Jul 5;5:18.
    Silymarin protects liver against toxic effects of anti-tuberculosis drugs in experimental animals.
    Eminzade S, Uraz F, Izzettin FV.
    Department of Pharmacology, Marmara University, Faculty of Pharmacy, Haydarpasa, Istanbul, Turkey. seminzade@hotmail.com.
    ABSTRACT: BACKGROUND: The first line anti-tuberculosis drugs isoniazid (INH), rifampicin (RIF) and pyrazinamide (PZA) continues to be the effective drugs in the treatment of tuberculosis, however, the use of these drugs is associated with toxic reactions in tissues, particularly in the liver, leading to hepatitis. Silymarin, a standard plant extract with strong antioxidant activity obtained from S. marianum, is known to be an effective agent for liver protection and liver regeneration. The aim of this study was to investigate the protective actions of silymarin against hepatotoxicity caused by different combinations of anti-tuberculosis drugs. METHODS: Male Wistar albino rats weighing 250-300 g were used to form 6 study groups, each group consisting of 10 rats. Animals were treated with intra-peritoneal injection of isoniazid (50 mg/kg) and rifampicin (100 mg/kg); and intra-gastric administration of pyrazinamid (350 mg/kg) and silymarin (200 mg/kg). Hepatotoxicity was induced by a combination of drugs with INH+RIF and INH+RIF+PZA. Hepatoprotective effect of silymarin was investigated by co-administration of silymarin together with the drugs. Serum biochemical tests for liver functions and histopathological examination of livers were carried out to demonstrate the protection of liver against anti-tuberculosis drugs by silymarin. RESULTS: Treatment of rats with INH+RIF or INH+RIF+PZA induced hepatotoxicity as evidenced by biochemical measurements: serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP) activities and the levels of total bilirubin were elevated, and the levels of albumin and total protein were decreased in drugs-treated animals. Histopathological changes were also observed in livers of animals that received drugs. Simultaneous administration of silymarin significantly decreased the biochemical and histological changes induced by the drugs. CONCLUSION: The active components of silymarin had protective effects against hepatotoxic actions of drugs used in the chemotherapy of tuberculosis in animal models. Since no significant toxicity of silymarin is reported in human studies, this plant extract can be used as a dietary supplement by patients taking anti-tuberculosis medications.
    PMID: 18601745 [PubMed - in process]

    Indian J Med Res. 2006 Nov;124(5):491-504.
    Hepatoprotective herbal drug, silymarin from experimental pharmacology to clinical medicine.
    Pradhan SC, Girish C.
    Department of Pharmacology, Jawaharlal Institute of Postgraduate Medical Education & Research, Pondicherry, India. scpradhan@jipmer.edu
    Silymarin, a flavonolignan from ‘milk thistle’ (Silybum marianum) plant is used almost exclusively for hepatoprotection and amounts to 180 million US dollars business in Germany alone. In this review we discuss about its safety, efficacy and future uses in liver diseases. The use of silymarin may replace the polyherbal formulations and will avoid the major problems of standardization, quality control and contamination with heavy metals or bacterial toxins. Silymarin consists of four flavonolignan isomers namely–silybin, isosilybin, silydianin and silychristin. Among them, silybin being the most active and commonly used. Silymarin is orally absorbed and is excreted mainly through bile as sulphates and conjugates. Silymarin offers good protection in various toxic models of experimental liver diseases in laboratory animals. It acts by antioxidative, anti-lipid peroxidative, antifibrotic, anti-inflammatory, membrane stabilizing, immunomodulatory and liver regenerating mechanisms. Silymarin has clinical applications in alcoholic liver diseases, liver cirrhosis, Amanita mushroom poisoning, viral hepatitis, toxic and drug induced liver diseases and in diabetic patients. Though silymarin does not have antiviral properties against hepatitis virus, it promotes protein synthesis, helps in regenerating liver tissue, controls inflammation, enhances glucuronidation and protects against glutathione depletion. Silymarin may prove to be a useful drug for hepatoprotection in hepatobiliary diseases and in hepatotoxicity due to drugs. The non traditional use of silymarin may make a breakthrough as a new approach to protect other organs in addition to liver. As it is having a good safety profile, better patient tolerability and an effective drug at an affordable price, in near future new derivatives or new combinations of this drug may prove to be useful.
    PMID: 17213517 [PubMed - indexed for MEDLINE]

    Drugs. 2001;61(14):2035-63.
    The use of silymarin in the treatment of liver diseases.
    Saller R, Meier R, Brignoli R.
    Abteilung Naturheilkunde, University Hospital Zurich, Switzerland.
    The high prevalence of liver diseases such as chronic hepatitis and cirrhosis underscores the need for efficient and cost-effective treatments. The potential benefit of silymarin (extracted from the seeds of Silybum marianum or milk thistle) in the treatment of liver diseases remains a controversial issue. Therefore, the objective of this review is to assess the clinical efficacy and safety of silymarin by application of systematic approach. 525 references were found in the databases, of which 84 papers were retained for closer examination and 36 were deemed suitable for detailed analysis. Silymarin has metabolic and cell-regulating effects at concentrations found in clinical conditions, namely carrier-mediated regulation of cell membrane permeability, inhibition of the 5-lipoxygenase pathway, scavenging of reactive oxygen species (ROS) of the R-OH type and action on DNA-expression, for example, via suppression of nuclear factor (NF)-kappaB. Pooled data from case record studies involving 452 patients with Amanita phalloides poisoning show a highly significant difference in mortality in favour of silibinin [the main isomer contained in silymarin] (mortality 9.8% vs 18.3% with standard treatment; p < 0.01). The available trials in patients with toxic (e.g. solvents) or iatrogenic (e.g. antispychotic or tacrine) liver diseases, which are mostly outdated and underpowered, do not enable any valid conclusions to be drawn on the value of silymarin. The exception is an improved clinical tolerance of tacrine. In spite of some positive results in patients with acute viral hepatitis, no formally valid conclusion can be drawn regarding the value of silymarin in the treatment of these infections. Although there were no clinical end-points in the four trials considered in patients with alcoholic liver disease, histological findings were reported as improved in two out of two trials, improvement of prothrombin time was significant (two trials pooled) and liver transaminase levels were consistently lower in the silymarin-treated groups. Therefore, silymarin may be of use as an adjuvant in the therapy of alcoholic liver disease. Analysis was performed on five trials with a total of 602 patients with liver cirrhosis. The evidence shows that, compared with placebo, silymarin produces a nonsignificant reduction of total mortality by -4.2% [odds ratio (OR) 0.75 (0.5 - 1.1)]; but that, on the other hand, the use of silymarin leads to a significant reduction in liver-related mortality of-7% [OR: 0.54 (0.3 - 0.9); p < 0.01]. An individual trial reported a reduction in the number of patients with encephalopathy of -8.7% (p = 0.06). In one study of patients with cirrhosis-related diabetes mellitus, the insulin requirement was reduced by -25% (p < 0.01). We conclude that available evidence suggests that silymarin may play a role in the therapy of (alcoholic) liver cirrhosis. Silymarin is has a good safety record and only rare case reports of gastrointestinal disturbances and allergic skin rashes have been published. This review does not aim to replace future prospective trials aiming to provide the 'final' evidence of the efficacy of silymarin.
    PMID: 11735632 [PubMed - indexed for MEDLINE]

    The list really goes on and on for the liver…

    BRAIN

    Food Chem Toxicol. 2009 Oct;47(10):2655-60. Epub 2009 Aug 6.
    Effect of silymarin on biochemical parameters of oxidative stress in aged and young rat brain.
    Galhardi F, Mesquita K, Monserrat JM, Barros DM.
    Instituto de Ciências Biológicas, Universidade Federal do Rio GrandeRio Grande, RS, Brazil.
    Silymarin (SM), the active complex of milk thistle, is a lipophilic fruit extract and is composed of several isomer flavonolignans. Flavonoids are antioxidants found molecules capable of intercepting reactive oxygen species (ROS). The oxidative stress (OS) is caused by imbalance between antioxidant defenses and production of ROS causing oxidative damage to macromolecules. Brain is susceptible to oxidative stress and it is associated with age-related brain dysfunction. This study evaluated the effect of SM on biochemical parameters that evaluate OS in aged and young rat brain. For measures of OS were used measures of total oxyradical scavenging capacity (ACAP) through the concentration of ROS by fluorescence, lipid peroxidation (LPO), via FOX and TBARS, proteins oxidation by Western blot (WB). Rats were treated with SM at doses of 200 and 400mg/kg/day (SM200 and SM400). The LPO analyzed through FOX was increased in the hippocampus of aged animals treated with SM400, but in the cortex of young and aged, the highest dose of SM decreased LPO analyzed through TBARS. Both doses have seemed most effective in the reduction of oxidized proteins in aged brain. These results suggest that SM may contribute to the prevention of aged-related and pathological degenerative processes in the brain.
    PMID: 19647779 [PubMed - indexed for MEDLINE]

    Br J Pharmacol. 2009 Aug;157(7):1270-7. Epub 2009 Jun 22.
    Silibinin prevents amyloid beta peptide-induced memory impairment and oxidative stress in mice.
    Lu P, Mamiya T, Lu LL, Mouri A, Zou L, Nagai T, Hiramatsu M, Ikejima T, Nabeshima T.
    Department of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, Meijo University, 150 Yagotoyama, Tempaku-ku, Nagoya, Japan.
    BACKGROUND AND PURPOSE: Accumulated evidence suggests that oxidative stress is involved in amyloid beta (Abeta)-induced cognitive dysfunction. Silibinin (silybin), a flavonoid derived from the herb milk thistle (Silybum marianum), has been shown to have antioxidative properties; however, it remains unclear whether silibinin improves Abeta-induced neurotoxicity. In the present study, we examined the effect of silibinin on the memory impairment and accumulation of oxidative stress induced by Abeta(25-35) in mice. EXPERIMENTAL APPROACH: Aggregated Abeta(25-35) (3 nmol) was intracerebroventricularly administered to mice. Treatment with silibinin (2, 20 and 200 mg.kg(-1), once a day, p.o.) was started immediately after the injection of Abeta(25-35). Locomotor activity was evaluated 6 days after the Abeta(25-35) treatment, and cognitive function was evaluated in a Y-maze and novel object recognition tests 6-11 days after the Abeta(25-35) treatment. The levels of lipid peroxidation (malondialdehyde) and antioxidant (glutathione) in the hippocampus were measured 7 days after the Abeta(25-35) injection. KEY RESULTS: Silibinin prevented the memory impairment induced by Abeta(25-35) in the Y-maze and novel object recognition tests. Repeated treatment with silibinin attenuated the Abeta(25-35)-induced accumulation of malondialdehyde and depletion of glutathione in the hippocampus. CONCLUSIONS AND IMPLICATIONS: Silibinin prevents memory impairment and oxidative damage induced by Abeta(25-35) and may be a potential therapeutic agent for Alzheimer's disease.
    PMID: 19552690 [PubMed - indexed for MEDLINE]

    J Pharmacol Exp Ther. 2009 Oct;331(1):319-26. Epub 2009 Jul 28.
    Silibinin attenuates amyloid beta(25-35) peptide-induced memory impairments: implication of inducible nitric-oxide synthase and tumor necrosis factor-alpha in mice.
    Lu P, Mamiya T, Lu LL, Mouri A, Niwa M, Hiramatsu M, Zou LB, Nagai T, Ikejima T, Nabeshima T.
    Department of Chemical Pharmacology, Meijo University, Nagoya, Japan.
    In Alzheimer's disease (AD), the deposition of amyloid peptides is invariably associated with oxidative stress and inflammatory responses. Silibinin (silybin), a flavonoid derived from the herb milk thistle, has potent anti-inflammatory and antioxidant activities. However, it remains unclear whether silibinin improves amyloid beta (Abeta) peptide-induced neurotoxicity. In this study, we examined the effect of silibinin on the fear-conditioning memory deficits, inflammatory response, and oxidative stress induced by the intracerebroventricular injection of Abeta peptide(25-35) (Abeta(25-35)) in mice. Mice were treated with silibinin (2, 20, and 200 mg/kg p.o., once a day for 8 days) from the day of the Abeta(25-35) injection (day 0). Memory function was evaluated in cued and contextual fear-conditioning tests (day 6). Nitrotyrosine levels in the hippocampus and amygdala were examined (day 8). The mRNA expression of inducible nitric-oxide synthase (iNOS) and tumor necrosis factor-alpha (TNF-alpha) in the hippocampus and amygdala was measured 2 h after the Abeta(25-35) injection. We found that silibinin significantly attenuated memory deficits caused by Abeta(25-35) in the cued and contextual fear-conditioning test. Silibinin significantly inhibited the increase in nitrotyrosine levels in the hippocampus and amygdala induced by Abeta(25-35). Nitrotyrosine levels in these regions were negatively correlated with memory performance. Moreover, real-time RT-PCR revealed that silibinin inhibited the overexpression of iNOS and TNF-alpha mRNA in the hippocampus and amygdala induced by Abeta(25-35). These findings suggest that silibinin (i) attenuates memory impairment through amelioration of oxidative stress and inflammatory response induced by Abeta(25-35) and (ii) may be a potential candidate for an AD medication.
    PMID: 19638571 [PubMed - indexed for MEDLINE]

    Bull Exp Biol Med. 2007 Dec;144(6):806-9.
    Effect of silimarin, succinic acid, and their combination on bioenergetics of the brain in experimental encephalopathy.
    Khazanov VA, Vengerovsky AI.
    Laboratory of Molecular Pharmacology, Institute of Pharmacology, Tomsk Research Center, Siberian Division of the Russian Academy of Medical Sciences.
    In rats with experimental encephalopathy caused by intoxication with 4-pentenoic acid inhibiting beta-oxidation of medium- and long-chain fatty acids, hepatoprotector silimarin inhibited LPO, prevented deenergization and maintained high respiratory activity of brain mitochondria, and increased the rate and coupling of oxidation and phosphorylation. Succinic acid improved oxidation of substrates in motochondria and promoted activation of succinate-dependent ATP generation. Silimarin and succinic acid used together produced a synergistic protective effect on brain mitochondria surpassing the protective effects of individual preparations and prevented LPO activation.
    PMID: 18856206 [PubMed - indexed for MEDLINE]

    J Surg Res. 2008 Apr;145(2):214-22. Epub 2007 Oct 22.
    Silymarin, the antioxidant component of Silybum marianum, prevents sepsis-induced acute lung and brain injury.
    Toklu HZ, Tunali Akbay T, Velioglu-Ogunc A, Ercan F, Gedik N, Keyer-Uysal M, Sener G.
    Department of Pharmacology, School of Pharmacy, Marmara University, Istanbul, Turkey.
    BACKGROUND: Sepsis is associated with enhanced generation of reactive oxygen species, which leads to multiple organ dysfunctions. Based on the potent antioxidant effects of silymarin, we investigated the putative protective role of silymarin against sepsis-induced oxidative damage in lung and brain tissues. MATERIALS AND METHODS: Sepsis was induced by cecal ligation and perforation (CLP). Sham and CLP groups received either vehicle or silymarin (50 mg/kg, p.o.) or 150 mg/kg i.p. N-acetylcysteine (NAC) for 10 days prior and immediately after the operation. Six hours after the surgery, rats were decapitated and blood was collected for the measurement of proinflammatory cytokines (tumor necrosis factor-alpha, interleukin-1 beta [IL-1 beta], and IL-6) levels, lactate dehydrogenase activity, and total antioxidant capacity. Lung and brain samples were taken for the measurement of malondialdehyde and glutathione levels, myeloperoxidase activity, thromboplastic activity, and also for histological assessment. Formation of reactive oxygen species in tissue samples was monitored by using chemiluminescence technique with luminol and lusigenin probe. RESULTS: Sepsis increased serum TNF-alpha, IL-1 beta, IL-6 levels, and lactate dehydrogenase activity and decreased total antioxidant capacity. On the other hand, tissue glutathione levels were decreased while malondialdehyde levels and myeloperoxidase activity were increased in both the lung and the brain tissues due to CLP. Furthermore, luminol and lucigenin chemiluminescence were significantly increased in the CLP group, indicating the presence of the oxidative damage. Silymarine and NAC treatment reversed these biochemical parameters and preserved tissue morphology as evidenced by histological evaluation. CONCLUSIONS: Silymarin, like NAC, reduced sepsis-induced remote organ injury, at least in part, through its ability to balance oxidant-antioxidant status, to inhibit neutrophil infiltration, and to regulate the release of inflammatory mediators.
    PMID: 17950327 [PubMed - indexed for MEDLINE]

    CANCER

    Antioxid Redox Signal. 2002 Aug;4(4):655-63.
    Flavonoid antioxidant silymarin and skin cancer.
    Singh RP, Agarwal R.
    Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado Health Sciences Center, Denver, CO 80262, USA.
    Oxidative stress is one of the key players in skin carcinogenesis, and therefore identifying nontoxic strong antioxidants to prevent skin cancer is an important area of research. In both animal and cell culture studies, we have shown that silymarin, a naturally occurring polyphenolic flavonoid antioxidant, exhibits preventive and anticancer effects against skin cancer. For example, silymarin strongly prevents both photocarcinogenesis and skin tumor promotion in mice, in part, by scavenging free radicals and reactive oxygen species and strengthening the antioxidant system. We also found that this effect of silymarin is by inhibiting endogenous tumor promoter tumor necrosis factor alpha in mouse skin, a central mediator in skin tumor promotion. In mechanistic studies, silymarin inhibits mitogenic and cell survival signaling and induces apoptosis. Furthermore, silymarin effectively modulates cell-cycle regulators and check points toward inhibition of proliferation, and growth arrest in G0-G1 and G2-M phases of the cell cycle. Thus, due to its mechanism-based chemopreventive and anticancer effects in experimental models, silymarin is an important candidate for the prevention and/or therapy of skin cancer, as well as other cancers of epithelial origin in humans.
    PMID: 12230878 [PubMed - indexed for MEDLINE]

    Integr Cancer Ther. 2007 Jun;6(2):130-45.
    Chemopreventive efficacy of silymarin in skin and prostate cancer.
    Deep G, Agarwal R.
    Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado Health Sciences Center, CO 80262, USA.
    Prevention and therapeutic intervention by phytochemicals are newer dimensions in the arena of cancer management. In this regard, the cancer chemopreventive role of silymarin (Silybum marianum) has been extensively studied and has shown anticancer efficacy against various cancer sites, especially skin and prostate. In skin cancer, silymarin treatment inhibits ultraviolet B radiation or chemically initiated or promoted carcinogenesis. These effects of silymarin against skin carcinogenesis have been attributed to its strong antioxidant and anti-inflammatory action as well as its inhibitory effect on mitogenic signaling. Similarly, silymarin treatment inhibits 3, 2-dimethyl-4-aminobiphenyl-induced prostate carcinogenesis and retards the growth of advanced prostate tumor xenograft in athymic nude mice. In prostate cancer, silymarin treatment down-regulates androgen receptor-, epidermal growth factor receptor-, and nuclear factor-kappaB- mediated signaling and induces cell cycle arrest. Extensive preclinical findings have supported the anticancer potential of silymarin, and now its efficacy is being evaluated in cancer patients.
    PMID: 17548792 [PubMed - indexed for MEDLINE]

    Int J Oncol. 2005 Jan;26(1):169-76.
    Silymarin and skin cancer prevention: anti-inflammatory, antioxidant and immunomodulatory effects (Review).
    Katiyar SK.
    Department of Dermatology, The University of Alabama at Birmingham, Birmingham, AL 35294, USA. skatiyar@uab.edu
    Several environmental and genetic factors are involved in skin cancer induction, however exposure to chemical carcinogens and solar ultraviolet (UV) radiation are primarily responsible for several skin diseases including skin cancer. Chronic exposure of solar UV radiation to the skin leads to basal cell and squamous cell carcinoma, and melanoma. Chemoprevention of skin cancer by consumption of naturally occurring botanicals appears a practical approach and therefore world-wide interest is considerably increasing to use these botanicals. Sunscreens are useful but their protection is not ideal because of inadequate use, incomplete spectral protection and toxicity. Silymarin, a plant flavonoid isolated from the seeds of milk thistle (Silybum marianum), has been shown to have chemopreventive effects against chemical carcinogenesis as well as photocarcinogenesis in various animal tumor models. Topical treatment of silymarin inhibited 7,12-dimethylbenz(a)anthracene-initiated and several tumor promoters, like 12-O-tetradecanoylphorbol-13-acetate, mezerein, benzoyal peroxide and okadaic acid, induced skin carcinogenesis in mouse models. Similarly, silymarin also prevented UVB-induced skin carcinogenesis. Wide range of in vivo mechanistic studies indicated that silymarin possesses antioxidant, anti-inflammatory and immunomodulatory properties which may lead to the prevention of skin cancer in in vivo animal models. The available experimental information suggests that silymarin is a promising chemopreventive and pharmacologically safe agent which can be exploited or tested against skin cancer in human system. Moreover, silymarin may favorably supplement sunscreen protection and provide additional anti-photocarcinogenic protection.
    PMID: 15586237 [PubMed - indexed for MEDLINE]

    Anticancer Agents Med Chem. 2009 Dec 16. [Epub ahead of print]
    Silibinin – A Promising New Treatment for Cancer.
    Cheung CW, Gibbons N, Johnson DW, Nicol DL.
    Departments of Renal Medicine, University of Queensland at Princess Alexandra Hospital, Brisbane, Queensland, Australia. catherine_cheung@health.qld.gov.au.
    Silymarin and its major constituent, Silibinin, are extracts from the medicinal plant Silybum marianum (milk thistle) and have traditionally been used for the treatment of liver diseases. Recently, these orally active, flavonoid agents have also been shown to exert significant anti-neoplastic effects in a variety of in vitro and in vivo cancer models, including skin, breast, lung, colon, bladder, prostate and kidney carcinomas. The aim of the present review is to examine the pharmacokinetics, mechanisms, effectiveness and adverse effects of silibinin's anti-cancer actions reported to date in pre-clinical and clinical trials. The review will also discuss the results of current research efforts seeking to determine the extent to which the effectiveness of silibinin as an adjunct cancer treatment is influenced by such factors as histologic subtype, hormonal status, stromal interactions and drug metabolising gene polymorphisms. The results of these studies may help to more precisely target and dose silibinin therapy to optimise clinical outcomes for oncology patients.
    PMID: 20015009 [PubMed - as supplied by publisher]

    Cancer Lett. 2008 Oct 8;269(2):352-62. Epub 2008 May 9.
    Multitargeted therapy of cancer by silymarin.
    Ramasamy K, Agarwal R.
    Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado Denver, 4200 East Ninth Street, Box C238, Denver, CO 80262, USA.
    Silymarin, a flavonolignan from milk thistle (Silybum marianum) plant, is used for the protection against various liver conditions in both clinical settings and experimental models. In this review, we summarize the recent investigations and mechanistic studies regarding possible molecular targets of silymarin for cancer prevention. Number of studies has established the cancer chemopreventive role of silymarin in both in vivo and in vitro models. Silymarin modulates imbalance between cell survival and apoptosis through interference with the expressions of cell cycle regulators and proteins involved in apoptosis. In addition, silymarin also showed anti-inflammatory as well as anti-metastatic activity. Further, the protective effects of silymarin and its major active constituent, silibinin, studied in various tissues, suggest a clinical application in cancer patients as an adjunct to established therapies, to prevent or reduce chemotherapy as well as radiotherapy-induced toxicity. This review focuses on the chemistry and analogues of silymarin, multiple possible molecular mechanisms, in vitro as well as in vivo anti-cancer activities, and studies on human clinical trials.
    [attachment=7694:nihms_72463_f0002.jpg]
    Free author's manuscript, a good read.

    BJU Int. 2007 Aug;100(2):438-44.
    Therapeutic value of orally administered silibinin in renal cell carcinoma: manipulation of insulin-like growth factor binding protein-3 levels.
    Cheung CW, Taylor PJ, Kirkpatrick CM, Vesey DA, Gobe GC, Winterford C, Nicol DL, Johnson DW.
    Department of Medicine, University of Queensland, Brisbane, Queensland, Australia.
    OBJECTIVES: To investigate if the feeding of silibinin (an anticancer flavonoid) to mice inhibits in vivo renal cell carcinoma (RCC) growth via changes in insulin-like growth factor binding protein-3 (IGFBP-3) levels. MATERIALS AND METHODS: Male severe combined immunodeficiency disease (SCID) mice (7 weeks old), with left kidneys injected with 1 million SN12K1 cells, were fed a silibinin-containing diet (0.1%, 0.2% and 0.4% w/w) or control AIN-93G diet for 39 days from 1 day after tumour engraftment. RESULTS: There was a reduction in tumour deposits and tumour kidney weight in SCID mice fed with a 0.4% silibinin-containing diet compared to those fed the control diet. Mice with tumour injection (silibinin or control-diet group) had constant total body weight and food consumption. The mean plasma and tumourous kidney silibinin concentrations, as measured by high-pressure liquid chromatography-tandem mass spectrometry, increased with escalating doses of silibinin. Using real-time polymerase chain reaction and enzyme-linked immunosorbent assay, the mean tissue IGFBP-3 mRNA (in SN12K1-implanted kidney) and plasma IGFBP-3 levels increased in mice fed with 0.1% silibinin (tumour IGFBP-3 mRNA levels, 156% higher vs control-diet group, P = 0.007; and plasma IGFBP-3 levels, 61% higher vs control-diet group, P = 0.002) but not in mice fed with the higher silibinin pellet strengths. CONCLUSION: Oral administration of silibinin suppressed local and metastatic tumour growth in vivo in an orthotopic xenograft model of RCC. This anti-neoplastic action of silibinin might involve IGFBP-3. The exact mechanism through which IGFBP-3 promotes silibinin's anticancer effects warrants further investigation.
    PMID: 17617146 [PubMed - indexed for MEDLINE]

    DIABETES/LIPIDS

    J Med Food. 2007 Sep;10(3):543-7.
    Silymarin as an adjunct to glibenclamide therapy improves long-term and postprandial glycemic control and body mass index in type 2 diabetes.
    Hussain SA.
    Department of Pharmacology and Toxicology, College of Pharmacy, University of Baghdad, Baghdad, Iraq. saad_alzaidi@yahoo.com
    Oxidative stress is increased postprandially and during long-term hyperglycemia in type 2 diabetic patients who present with poor response to glibenclamide. This study was designed to evaluate the effects of the antioxidant flavonoid silymarin in improving long-term and postprandial glycemic and weight control in type 2 diabetic patients treated with glibenclamide. Using a randomized, double-blind, placebo-controlled design, 59 type 2 diabetic patients, previously maintained on 10 mg/day glibenclamide and diet control, with poor glycemic control, were randomized into three groups: the first two groups were treated with either 200 mg/day silymarin or placebo as adjuncts to glibenclamide, and the third group was maintained on glibenclamide alone for 120 days. Fasting and 4-hour postprandial plasma glucose, glycated hemoglobin (HbA(1c)), and body mass index (BMI) were evaluated at baseline and after 120 days. Compared with placebo, silymarin treatment significantly reduced both fasting and postprandial plasma glucose excursions, in addition to significantly reducing HbA(1c) levels and BMI after 120 days. No significantly different effects were observed for placebo compared to glibenclamide alone. In conclusion, adjunct use of silymarin with glibenclamide improves the glycemic control targeted by glibenclamide, during both fasting and postprandially, an effect that may be related to increased insulin sensitivity in peripheral tissues.
    PMID: 17887949 [PubMed - indexed for MEDLINE]

    Phytother Res. 2006 Dec;20(12):1036-9.
    The efficacy of Silybum marianum (L.) Gaertn. (silymarin) in the treatment of type II diabetes: a randomized, double-blind, placebo-controlled, clinical trial.
    Huseini HF, Larijani B, Heshmat R, Fakhrzadeh H, Radjabipour B, Toliat T, Raza M.
    Department of Pharmacology, Institute of Medicinal Plants, ACECR Tehran, Iran. huseini_fallah@yahoo.com
    Oxidative stresses are increasingly implicated in the pathogenesis of diabetic complications which may either cause direct pancreatic beta-cell damage or lead to metabolic abnormalities that can induce or aggravate diabetes. The valuable effect of antioxidant nutrients on the glycemic control of diabetic patients has been reported in experimental and clinical studies. The present study was designed to investigate the effects of the herbal medicine, Silybum marianum seed extract (silymarin), which is known to have antioxidant properties on the glycemic profile in diabetic patients. A 4-month randomized double-blind clinical trial was conducted in 51 type II diabetic patients in two well-matched groups. The first group (n = 25) received a silymarin (200 mg) tablet 3 times a day plus conventional therapy. The second group (n = 26) received the same therapy but a placebo tablet instead of silymarin. The patients were visited monthly and glycosylated hemoglobin (HbA(1)c), fasting blood glucose (FBS), insulin, total cholesterol, LDL and HDL, triglyceride, SGOT and SGPT levels were determined at the beginning and the end of the study. The results showed a significant decrease in HbA(1)c, FBS, total cholesterol, LDL, triglyceride SGOT and SGPT levels in silymarin treated patients compared with placebo as well as with values at the beginning of the study in each group. In conclusion, silymarin treatment in type II diabetic patients for 4 months has a beneficial effect on improving the glycemic profile.
    PMID: 17072885 [PubMed - indexed for MEDLINE]

    Diabetes Nutr Metab. 2002 Aug;15(4):222-31.
    Silybin-beta-cyclodextrin in the treatment of patients with diabetes mellitus and alcoholic liver disease. Efficacy study of a new preparation of an anti-oxidant agent.
    Lirussi F, Beccarello A, Zanette G, De Monte A, Donadon V, Velussi M, Crepaldi G.
    Department of Medical and Surgical Sciences, University of Padova, Italy. flavio.lirussi@unipd.it
    BACKGROUND AND AIMS: In patients with non-insulin dependent diabetes mellitus (T2DM) and associated chronic liver disease, plasma levels of glucose, insulin and triglycerides are high, lipid peroxidation is increased and natural antioxidant reserves are reduced. Thus, we hypothesised that the re-balancing of cell redox levels and amelioration of liver function could result in a better glucose and lipid metabolism. To study this, we assessed the effect of a new oral formulation of an antioxidant agent – silybin-beta-cyclodextrin (named IBI/S) – in patients with chronic alcoholic liver disease and concomitant T2DM. METHODS: Sixty outpatients were enrolled in a three-centre, double blind, randomised, IBI/S vs placebo study. Forty-two (21 in the group IBI/S – 135 mg/d silybin per os – and 21 in the placebo group) concluded the 6-month treatment period. The efficacy parameters included fasting and mean daily plasma glucose levels, glycosylated hemoglobin (HbA1c), basal, stimulated C-peptide and insulin levels, total-, HDL-cholesterol and triglycerides levels in addition to conventional liver function tests. Insulin sensitivity was estimated by HOMA-IR. Malondialdehyde (MDA) was also measured before and after treatment as an index of oxidative stress. RESULTS: Fasting blood glucose levels, which were similar at baseline in IBI/S group and in the placebo group (173.9 mg/dl and 177.1 mg/dl, respectively), decreased to 148.4 mg/dl (-14.7% vs baseline; p = 0.03) in the IBI/S group while they were virtually unchanged in the placebo group. The comparison between the groups at mo 6 (T6) also showed a significant reduction of glucose levels in the IBI/S group (p = 0.03). The same trend was observed in mean daily blood glucose levels, HbA1c and HOMA-IR, although differences were not significant. Basal and stimulated C-peptide values showed that only a few changes had occured in both groups. Such results indicate that insulin secretion was virtually unaffected, as confirmed also by the insulinemia data. Plasma triglycerides concentrations dropped from a baseline value of 186 mg/dl to 111 mg/dl (T6) in the IBI/S group, with significant differences at all instances with respect to baseline values. By contrast, triglycerides increased from 159 mg/dl at entry to 185 mg/dl (T6) in the placebo group. The difference between the groups at T6 was highly significant (p < 0.01). Total and HDL cholesterol as well as liver function tests did not change significantly during the study in both groups. MDA decreased significantly only in the group receiving IBI/S. No clinically relevant side effects were observed in either group. CONCLUSIONS: Oral administration silybin-beta-cyclodextrin in patients with T2DM and compensated chronic alcoholic liver disease causes a significant decrease in both glucose and triglyceride plasma levels. These effects may be due to the recovery of energy substrates, consistent with a reduced lipid peroxidation and an improved insulin activity.
    PMID: 12416659 [PubMed - indexed for MEDLINE]

    J Hepatol. 1997 Apr;26(4):871-9.
    Long-term (12 months) treatment with an anti-oxidant drug (silymarin) is effective on hyperinsulinemia, exogenous insulin need and malondialdehyde levels in cirrhotic diabetic patients.
    Velussi M, Cernigoi AM, De Monte A, Dapas F, Caffau C, Zilli M.
    Anti-Diabetes Centre, Monfalcone Hospital, Gorizia, Italy.
    BACKGROUND/AIMS: Several studies have demonstrated that diabetic patients with cirrhosis require insulin treatment because of insulin resistance. As chronic alcoholic liver damage is partly due to the lipoperoxidation of hepatic cell membranes, anti-oxidizing agents may be useful in treating or preventing damage due to free radicals. The aim of this study was to ascertain whether long-term treatment with silymarin is effective in reducing lipoperoxidation and insulin resistance in diabetic patients with cirrhosis. METHODS: A 12-month open, controlled study was conducted in two well-matched groups of insulin-treated diabetics with alcoholic cirrhosis. One group (n=30) received 600 mg silymarin per day plus standard therapy, while the control group (n=30) received standard therapy alone. The efficacy parameters, measured regularly during the study, included fasting blood glucose levels, mean daily blood glucose levels, daily glucosuria levels, glycosylated hemoglobin (HbA1c) and malondialdehyde levels. RESULTS: There was a significant decrease (p<0.01) in fasting blood glucose levels, mean daily blood glucose levels, daily glucosuria and HbA1c levels already after 4 months of treatment in the silymarin group. In addition, there was a significant decrease (p<0.01) in fasting insulin levels and mean exogenous insulin requirements in the treated group, while the untreated group showed a significant increase (p<0.05) in fasting insulin levels and a stabilized insulin need. These findings are consistent with the significant decrease (p<0.01) in basal and glucagon-stimulated C-peptide levels in the treated group and the significant increase in both parameters in the control group. Another interesting finding was the significant decrease (p<0.01) in malondialdehyde/levels observed in the treated group. CONCLUSIONS: These results show that treatment with silymarin may reduce the lipoperoxidation of cell membranes and insulin resistance, significantly decreasing endogenous insulin overproduction and the need for exogenous insulin administration.
    PMID: 9126802 [PubMed - indexed for MEDLINE]

    KIDNEYS

    Invest New Drugs. 2009 Jul 10. [Epub ahead of print]

    Dietary supplementation of silymarin protects against chemically induced nephrotoxicity, inflammation and renal tumor promotion response.
    Kaur G, Athar M, Alam MS.

    Department of Chemistry, Faculty of Science, Jamia Hamdard, Hamdard Nagar, New Delhi, 110062, India, gurpreet6@yahoo.com.

    Ferric nitrilotriacetate (Fe-NTA) is a potent nephrotoxicant and a renal carcinogen that induces its effect by causing oxidative stress. The present study was undertaken to explore protective effect of silymarin, a flavonolignan from milk thistle (Silybum marianum), against Fe-NTA mediated renal oxidative stress, inflammation and tumor promotion response along with elucidation of the implicated mechanism(s). Administration of Fe-NTA (10 mg/kg bd wt, i.p.) to Swiss albino mice induced marked oxidative stress in kidney, evident from augmentation in renal metallothionein (MT) expression, depletion of glutathione content and activities of antioxidant and phase II metabolizing enzymes, and enhancement in production of aldehyde products such as 4-hydroxy-2-nonenal. Fe-NTA also significantly activated nuclear factor kappa B (NFkappaB) and upregulated the expression of downstream genes: cyclooxygenase 2 and inducible nitric oxide synthase and enhancing the production of proinflammatory cytokines: tumor necrosis factor alpha (TNF-alpha) and interleukin-6 (IL-6). However, feeding of 0.5% and 1% silymarin diet conferred a significant protection against Fe-NTA induced oxidative stress and inflammation. It further augmented MT expression, restored the antioxidant armory, ameliorated NFkappaB activation and decreased the expression of proinflammatory mediators. Silymarin also suppressed Fe-NTA induced hyperproliferation in kidney, ameliorating renal ornithine decarboxylase activity and DNA synthesis. From these results, it could be concluded that silymarin markedly protects against chemically induced renal cancer and acts plausibly by virtue of its antioxidant, anti-inflammatory and antiproliferative activities.

    PMID: 19590824 [PubMed - as supplied by publisher

    Food Chem Toxicol. 2008 Jul;46(7):2422-8. Epub 2008 Apr 7.

    Silymarin prevents adriamycin-induced cardiotoxicity and nephrotoxicity in rats.
    El-Shitany NA, El-Haggar S, El-desoky K.

    Department of Pharmacology and Toxicology, College of Pharmacy, Tanta University, Tanta, Egypt. Nagla_fouad@yahoo.com

    Adriamycin is a potent anticancer agent, its clinical use is limited for its marked cardiotoxicity and nephrotoxicity. The present study aimed to investigate the possible protective role of the natural antioxidant silymarin on ADR-induced heart and kidney toxicity. Studies were performed on four groups of rats. 1--control group, 2--silymarin group (50 mg/kg), 3--adriamycin group (10 mg/kg), 4--adriamycin+silymarin group. On the third day after ADR injection, plasma was separated for determination of LDH, CPK, cholesterol and total lipids. 30 days after ADR injection, plasma was separated for determination of creatinine and urea levels. Frozen heart specimens (72 h) and frozen kidney specimens (30days) were used for estimation of lipid peroxides and GSH contents. Histopathological examinations of heart and kidney sections were also done. Pretreatment of ADR-treated rats with silymarin resulted in a significant decrease in the plasma CPK, LDH, creatinine and urea. On the other hand silymarin pretreatment did not change ADR-induced hyperlipidemia. Silymarin pretreatment significantly decreased the myocardial MDA contents. In addition, silymarin pretreatment normalized renal tissue contents of MDA and GSH. Histopathological examination of heart and kidney sections revealed that ADR caused only mild myocardial injury in silymarin pretreated rats. Also, silymarin pretreatment inhibited ADR-induced renal tubular damage in rats. These results have suggested that, silymarin ameliorated ADR-induced cardiotoxicity and protected against ADR-induced nephrotoxicity in male albino rats. The mechanisms of silymarin induced protection against ADR-induced toxicities were proved to be due to inhibition of lipid peroxidation and protection against GSH depletion.

    PMID: 18487002 [PubMed - indexed for MEDLINE

    World J Urol. 2008 Aug;26(4):401-7. Epub 2008 Apr 12.
    Silymarin attenuates the renal ischemia/reperfusion injury-induced morphological changes in the rat kidney.
    Senturk H, Kabay S, Bayramoglu G, Ozden H, Yaylak F, Yucel M, Olgun EG, Kutlu A.
    Faculty of Science, Department of Biology, Osmangazi University, Eskisehir, Turkey. hsenturk@ogu.edu.tr
    OBJECTIVES: Renal ischemia/reperfusion (I/R) injury is associated with increased mortality and morbidity rates due to acute renal failure (ARF). Oxidative stress induced with renal I/R injury directly affects glomerular and tubular epithelium through reactive oxygen species. Several studies have been directed to the treatment of renal I/R injury. The aim of this study was to test the attenuation with silymarin (SM) treatment of renal I/R injury-induced morphological changes in the rat kidney. METHODS: A total of 32 adult male Sprague-Dawley rats were evaluated in four groups. Group I (sham), Group II (renal I/R), Group III (renal I/R injury + SM 50 mg per kg) and Group IV (renal I/R injury + SM 100 mg per kg) were designed to evaluate the dose-dependent effects of SM on the morphological changes of renal I/R injury. Renal I/R injury were induced with left renal pedicle occlusion for 45 min followed with reperfusion for 6 h under anesthesia. After induction of I/R injury, left nephrectomies were performed for histopathological examinations. RESULTS: After renal I/R injury, significant tubular dilatation, tubular vacuolization, pelvic inflammation, interstitial inflammation, perirenal adipose infiltration, tubular necrosis and glomerular necrosis (cortical necrosis) were observed. However, even with low dose SM in Group III (50 mg per kg SM), histopathological changes due to I/R injury were prevented. CONCLUSIONS: The results of this study have demonstrated that SM significantly prevents renal I/R injury-induced renal tubular changes in the rat. SM in 50 mg/kg was observed to be sufficient to significantly prevent renal tubular necrosis. Further, to our literature knowledge, this is the first specific study to demonstrate the preventive effect of SM on renal I/R injury.
    PMID: 18408933 [PubMed - indexed for MEDLINE]

    ok, it's in vitro I know, but,

    Stimulatory Effects of Silibinin and Silicristin from the Milk Thistle Silybum marianum on Kidney Cells
    1. Johann Sonnenbichler1,
    2. Fortunato Scalera1,
    3. Isolde Sonnenbichler1 and
    4. Roland Weyhenmeyer2
    1. 1Max Planck Institute for Biochemistry, Martinsried, Germany (J.S., F.S., I.S.); and 2Madaus AG, Köln, Germany (R.W.)
    The biochemical influence of flavonolignans from the milk thistleSilybum marianum has been tested on kidney cells of African green monkeys. Two nonmalignant cell lines were selected, with the focus of the work on the fibroblast-like Vero line. Proliferation rate, biosynthesis of protein and DNA, and the activity of the enzyme lactate dehydrogenase (as a measure of the cellular metabolic activity) were chosen as parameters for the effect of the flavonolignans. Silibinin and silicristin show remarkable stimulatory effects on these parameters, mainly in Vero cells; however, isosilibinin and silidianin proved to be inactive. In vitro experiments with kidney cells damaged by paracetamol, cisplatin, and vincristin demonstrated that administration of silibinin before or after the chemical-induced injury can lessen or avoid the nephrotoxic effects. The results warrant in vivo evaluations of the flavonolignan derivatives.

    OTHER

    Cellular and Molecular Life Sciences
    Silibinin, a plant extract with antioxidant and membrane stabilizing properties, protects exocrine pancreas from cyclosporin A toxicity
    J. v. Scho¨ nfelda,*, B. Weisbrodb and M. K. Mu¨ llerc

    Silymarin can be extracted from the milk thistle, and silibinin is the main component of the plant extract. Possibly due to their antioxidant and membrane-stabilizing properties, the compounds have been shown to protect different organs and cells against a number of insults. Thus liver, kidney, erythrocytes and platelets have been protected from the toxic effects of ethanol, carbon tetrachloride, cold ischemia and drugs, respectively. The effect of silibinin on endocrine and exocrine pancreas, however, has not been studied. We therefore investigated whether silibinin treatment attenuates cyclosporin A (CiA) toxicity on rat endocrine and exocrine pancreas. Groups of 15 male Wistar rats were treated for 8 days with CiA and/or silibinin. On day 9, endocrine and exocrine pancreatic functions were tested in vitro. At the end of the treatment period, blood glucose levels in vivo were significantly higher in rats treated with CiA, while silibinin did not affect glucose levels. In vitro, insulin secretion was inhibited after treatment with silibinin, but amylase secretion was not affected. After treatment with CiA both insulin and amylase secretion were reduced. Silibinin and CiA had an additive inhibitory effect on insulin secretion, but silibinin attenuated CiA-induced inhibition of amylase secretion. Despite CiA treatment, amylase secretion was in fact restored to normal with the highest dose of silibinin. Thus silibinin inhibits glucose-stimulated insulin release in vitro, while not affecting blood glucose concentration in vivo. This combination of effects could be useful in the treatment of non-insulin-dependent diabetes mellitus. Furthermore, silibinin protects the exocrine pancreas from CiA toxicity. As this inhibitory effect is probably unspecific, silibinin may also protect the exocrine pancreas against other insult principles, such as alcohol.
    Free full text.

    Toxicol In Vitro. 2008 Apr;22(3):610-7. Epub 2007 Dec 8.
    Assessment of drug-drug interaction for silymarin.
    Doehmer J, Tewes B, Klein KU, Gritzko K, Muschick H, Mengs U.
    GenPharmTox Biotech AG, Fraunhofer Str. 9, D-82152 Planegg/Martinsried, Germany. johannes.doehmer@genpharmtox.de
    Silymarin was assessed for drug-drug interaction by permeability studies with Caco-2 cells, for cytochrome P450 induction with human primary hepatocytes and for cytochrome P450 inhibition with human liver microsomes. Studies with Caco-2 cells revealed no interference of silymarin with the permeability of nifedipine. Silymarin did not induce cytochromes P450 2C9 and 3A4 at concentrations of 0.1; 1; and 100 microM, measured as silibinin. The inhibitory effect was tested on the nine major cytochromes P450 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4 at concentrations of 1 and 100 microM silymarin. At 1 microM concentration no or negligible inhibition of cytochromes P450 1A2, 2A6, 2B6, 2C8, 2C9, and 2E1, minor inhibition of 3A4 (<20%), and moderate inhibition of 2C19 and 2D6 (50% of the cytochromes P450 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4 was observed, and no or moderate inhibition was for the cytochromes P450 1A2, 2A6, and 2E1. However, in view of the clinically relevant plasma concentration of approx. 0.2 microM measured as silibinin, it is evident that there is no drug-drug interaction problem with silymarin.
    PMID: 18249085 [PubMed - indexed for MEDLINE]

    Effects of Silymarin on the Acute Stage of the Trinitrobenzenesulphonic Acid Model of Rat Colitis

    Torcuata Cruz, Julio Gálvez*, Esperanza Crespo, M. Angeles Ocete, Antonio Zarzuelo
    Department of Pharmacology, School of Pharmacy, University of Granada, Granada, Spai
    Abstract
    The intestinal anti-inflammatory activity of several doses of silymarin was tested in the acute stage of the trinitrobenzenesulfonic acid (TNBS) model of rat colitis. The results obtained show that oral pre-treatment with 50 mg/kg of silymarin significantly attenuated macroscopic colonic damage as well as reduced colonic myeloperoxidase activity compared to non-treated colitic animals. The beneficial effect was accompanied by an improvement in the colonic oxidative status, which was altered in colonic inflammation, by preventing glutathione depletion and reducing malonyldialdehyde production. This suggests that the well known antioxidant properties of silymarin can participate in its intestinal anti-inflammatory activity. In addition, a preservation in the colonic absorptive function was also observed, and this effect can also account for the colonic protective effect observed in this model of acute colitis.

    Central European Journal of Biology
    On the benefits of silymarin in murine colitis by improving balance of destructive cytokines and reduction of toxic stress in the bowel cells
    Hadi Esmaily1, Azadeh Hosseini-Tabatabaei1, Reza Rahimian1, Reza Khorasani1, Maryam Baeeri1, Ahmadreza Barazesh-Morgani1, Nargues Yasa2, Yassaman Khademi1 and Mohammad Abdollahi1

    Abstract Inflammatory bowel disease (IBD) is a multifactorial disease with an unknown etiology characterized by oxidative stress, leucocyte infiltration and a rise in inflammatory cytokines. In this study, we have investigated the effects of silymarin, a mixture of several flavonolignans with established antioxidant and anti-inflammatory properties, on trinitrobenzene sulphonic acid (TNBS)-induced colitis in rats. Experimental colitis was induced in male Wistar-albino rats by delivering TNBS to the distal colon. All the medicines were administered by gavage for seven days. Thirty-six male rats were divided into six groups containing six rats in each one. Control rats received only TNBS. In the treated groups, animals were given different doses of silymarin (40, 80, and 160 mg/kg). Dexamethasone (1 mg/kg) was used as the positive treatment. Colonic status was investigated seven days post induction of colitis through macroscopic, histological, and biochemical analyses. Amelioration of the morphological signs including macroscopic damage, necrotic area, and histology were seen subsequent to treating animals with silymarin. These observations were accompanied by a significant reduction in the degree of both neutrophil infiltration, indicated by decreased myeloperoxidase activity, and lipid peroxidation, as measured by a decline in malodialdehyde content in inflamed colon as well as a decrease in levels of inflammatory cytokines (TNF-α and IL-1β). The results of the present study reveal that the beneficial effect of silymarin in bowel cells is mediated through its anti-oxidant and anti-inflammatory potentials.

  41. Re # sdavis2on 18 Jun 2011 at 1:53 pm:
    Seems this blog is heavily biased toward showing failures and not successes. No wonder there aren’t more visitors.
    But I wouldn’t expect to see any from a site that claims green tea, milk thistle or turmeric don’t exhibit any significant clinical benefit and refers to the “Natural Medicines Comprehensive Database” (ha!) to figure out what they do. What a laugh! Time to study science again, guys.

    I think you’re sadly mistaken – I am a huge proponent of the study of dietary herbal supplements. Since you appear to have facility with PubMed, why not do a search for “Kroll DJ” and “silibinin” – here, let me help:

    http://www.ncbi.nlm.nih.gov/pubmed?term=kroll%20dj%20AND%20silibinin

    But even with my enthusiasm for milk thistle extracts, a major hurdle to overcome is the bioavailability of the active compounds. The aromatic hydroxyls are very good sites for glucuronidation and the parent compounds are not absorbed well. Attempts to improve bioavailability with formulations (such as with phosphatidylcholine) are one approach but semi-synthetic analogs are likely going to be necessary to overcome the Phase II metabolism issues.

  42. Harriet Hall says:

    @sdavis2,

    An impressive exercise in cherry-picking.

    Try using PubMed’s “clinical queries” function and searching for systematic reviews of milk thistle. Not so impressive. For instance, a Cochrane review concluded “Our results question the beneficial effects of milk thistle for patients with alcoholic and/or hepatitis B or C virus liver diseases and highlight the lack of high-quality evidence to support this intervention.”

  43. Scott says:

    Well guys, since you can’t seem to figure it out how to do it on your own (doubtful)

    It’s the responsibility of the person making the claim to provide the citations. Expecting us to guess which particular ones you were relying upon, even assuming that you had any at all, is rather silly.

    And for future reference, PMIDs and (perhaps) titles is a much more compact way to provide citations; including the abstracts, etc. simply produces a wall of text.

  44. nybgrus says:

    also, listing a set of PMIDs (as Dr. Hall pointed out) is pointless. A single study does not a point make. Besides, what is the point of posting here if all you are going to do is that? Make your argument, have it be intelligent and cogent, and cite when necessary. Usually when people here ask for citations it is because you are not making a sound argument (or in your case, one at all). I don’t often get asked for citations here, but when I do I provide them and offer the context.

  45. sdavis2 says:

    @Harriet, I wasn’t the one doing the cherry-picking. The majority of the published studies I researched show positive results. Cochrane only included 13 trials and only for end-stage diseases using low-dose silymarin. Now, I understand the Cochrane Collaboration has a good reputation among the medical community, however, what they were basically asking for was failure. End-stage diseases such as these are incurable – unless we cure aging first.

    But what about silymarin’s efficacy at prevention and reversal of mild disease? Well, again, I see very promising results.

    @David J Kroll, Indeed bioavailability with silymarin is an issue, isn’t it? But haven’t higher-dose trials shown success? That’s what I’ve seen. Correct me if I’m wrong?

  46. Harriet Hall says:

    @sdavis2,

    The Natural Medicines Comprehensive Database is not known for cherry-picking. It rates milk thistle as “likely safe” and “possibly effective” for diabetes and dyspepsia but “insufficient reliable evidence” to rate its effectiveness for other conditions. It also lists a number of minor to moderate interactions with other drugs. It includes 18 references in the effectiveness section as well as many more in the section on mechanism of action.

    I would concur with you that the results are “promising.” But I think it’s premature to draw any conclusions.

  47. Imadgeine says:

    Re: “Wish someone would come up food that would cure hot flushes!

    Yes Scott the point you make about HRT etc had not escaped me. Hence my avoidance of black cohosh and other herbs.
    But if you had been suffering from hot flushes for 10 years and you were advised against HRT due to breast cancer history, you would wish there was a magic cure you could sprinkle on your cereal as well :)

Comments are closed.