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Old drugs, new tricks

What does honey bee colony collapse disorder have to do with a potential new cancer treatment?

They both relate – in a convoluted manner – to an old antibacterial drug called nitroxoline.

True to my devotion as a natural product pharmacologist, I’m proud to say that new life would not have come to nitroxoline had not a fungal natural product called fumagillin been studied as an antiangiogenic anticancer drug – one that inhibits the formation of new blood vessels.

Let’s step back for a moment. Fumagillin, was first isolated as an antibiotic in 1949 from a culture of Aspergillus fumigatus. Most recently, fumagillin has been used in honey bee hives as an antiparasitic drug to control the microsporidium parasite, Nosema cerenae. You might recognize the name of this parasite from the controversial PLoS One paper last year by Jerry Bromenshenk’s group at Montana who hypothesized that the parasite synergizes with the iridovirus IIV to cause colony collapse disorder. (Disclosure: I write a blog at PLoS Blogs network, operated by the publisher of PLoS One).

Bee that as it may (pun intended), fumagillin was serendiptously identified again in 1990 by a group led by the late antiangiogenesis pioneer, Dr. Judah Folkman. (Note to the reader: I’m treading here on the expert ground of SBM editor Dr. David Gorski, so I’m sure he’ll weigh in to correct me somewhere herein).

In their Nature paper, Folkman’s group found Aspergillus fumigatus as a contaminant of a culture of capillary endothelial cells and noted that it caused cell rounding similar to other angiogenesis inhibitors. Indeed, the fungus was secreting fumagillin. However, fumagillin itself had too much systemic toxicity when used in mouse models of human cancer. So, with colleagues from the Japanese drug company Takeda, the group synthesized analogs of fumagillin, the most active of which was a compound called AGM-1470 or, later, TNP-470. However, the drug suffered from a poor bioavailability when taken orally and a short half-life in clinical trials. Folkman’s group continued to work on a new formulation of TNP-470 described in a 2008 Nature Biotechnology paper that appeared after he passed away at age 74.

Most noteworthy about fumagillin and its analogs was that they revealed an entirely new way of halting the growth of endothelial cells in tumors. In 1997, the laboratory of Craig Crews at Yale University took advantage of a chemically reactive group on the fumagillin molecule – an epoxide – to purify from human umbilical vein endothelial cells (HUVEC) a protein that was bound by the drug. As detailed in this PNAS paper, the drug’s target turned out to be a metalloproteinase called methionine aminopeptidase-2, or MetAP2. A group led by Jun Liu, then at MIT, demonstrated that TNP-470 also targeted this enzyme which acts by cleaving the initial methonine residue from a subset of proteins.

Most recently, Liu’s group, now at Johns Hopkins School of Medicine, screened a library of 175,000 compounds for agents capable of inhibiting MetAP-2 in parallel with another group of approved drugs from all therapeutic classes. Emerging from both of these screens was nitroxoline, a drug used to treat urinary tract infections in South Africa (PDF) as early as 1978, sold under the trade name, Nicene-N.

In the Liu group’s most recent paper appearing in November 2010 in the Journal of the National Cancer Institute, nitroxoline was investigated for its antiangiogenic activity against human xenografts of breast and bladder cancer in mice. At doses similar to those given to humans, nitroxoline had good efficacy – but not hugely impressive – in slowing tumor growth and inhibiting microvessel formation both models. The activity against the bladder cancer was interesting since the tumor cells were implanted orthotopically (in the bladder) rather than in the subcutaneous tissue of the animal. Why bladder cancer? Because over 70% of the administered dose of nitroxoline in humans accumulates in the bladder. These findings are, of course, preliminary – the investigators only used one dose of the drug in this work and did not try to combine it with any other commonly used chemotherapeutic drug.

Usually, I don’t get too excited about a drug with activity against human tumor xenografts until it shows good pharmacokinetic properties in people. However, nitroxoline has been used clinically and already has a history of safe human use. Repurposing old drugs with activity against novel targets presents a lower barrier of risk for pharmaceutical development when compared with an exciting novel compound of unknown human safety and bioavailability. Such compounds are more likely to proceed to clinical trials – although nitroxoline is not currently approved in the US, its approval elsewhere is likely to speed human studies.

No, no, nitroxoline will not be a cure for cancer. But it does provide a lesson of the value of natural products in the identification of new cellular targets. Nitroxoline’s antiangiogenic activity would not have been discovered had fumagillin not been identified as a MetAP2 inhibitor. And further study of nitroxoline has revealed that it has an additional activity not shared by TNP-470: it also inhibits the SIRT1 class of histone deacetylases. This finding opens another avenue for the study of SIRT1 inhibitors with agents that target MetAP2.

Posted in: Basic Science, Cancer, History, Pharmaceuticals

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45 thoughts on “Old drugs, new tricks

  1. There is a vast difference between legitimate natural product pharmacology, as exemplified in this post, and the kind of herbalism that is identified with “CAM” and, at least until recently, with research deemed acceptable to the NCCAM.

    Dr. Kroll has written of his frustrations in seeking NCCAM grants: he was accused of “lend[ing] a drug development aspect to an otherwise ‘herbal’ application.” This is unsurprising, considering the views of those that the NCCAM considers to be its special constituents (scroll down to the words of naturopath Thomas Kruzel).

    Dr. Kroll, have you noticed any difference recently? Last winter, Director Josephine Briggs promised that things would change.

    1. Dr. Atwood (comment #1), indeed, I’m quite optimistic with the new leadership of Dr. Briggs – a long way from when my colleagues and I had some philosophical and scientific issues with the agency in the early 2000s.

      You search the NIH RePORTER database and query for active grants only under NCCAM – on the upper right of this page I selected active projects on the line for Fiscal Year and NCCAM two lines down under Agency/Institute/Center. You’ll get 570 projects and, by and large, they are of a much higher level of scientific rigor than ten years ago. Sure, there are a few zingers in there but I’m increasingly pleased with NCCAM’s funding portfolio.

  2. windriven says:

    Who says science isn’t exciting? Thanks for a terrific story of dedicated men and women teasing through years of difficult research to advance the cause of science and lay another brick in the wall against cancer.

    “Most recently, Liu’s group, now at Johns Hopkins School of Medicine, screened a library of 175,000 compounds for agents capable of inhibiting MetAP-2 in parallel with another group of approved drugs from all therapeutic classes”

    This stands in stark contrast to those who peddle magic water and shamanistic rituals. The words ignorant, lazy and credulous leap to mind.

  3. Gaythia says:

    I am personally acquainted with the Colorado beekeeper described by Melody Voith here: http://cenblog.org/cleantech-chemistry/2010/12/epa-memo-reignites-honey-bee-controversy/

    Thus, I believed that the honey bee colony collapse syndrome might be caused by over-indulgence in corn products, something that in a largely unrelated manner is also negatively affecting the waistlines, and thus the health of some of the rest of us.

    I realize that the matter that interests you, as a pharmacist is the drug, nitroxoline, and it’s potential as a cancer treatment.

    But what I would like to know is: Is there something perhaps about the Clothianidin pesticide that might weaken honeybee immune systems and leave them susceptable to the Aspergillus fumigatus fungus or are these two unrelated hypotheses?

  4. Ben Kavoussi says:

    @ Kimball Atwood. You are absolutely right. What David Kroll describes here is simply pharmacognosy, which is entirely based on the biochemistry on natural products and their pharmacoactive properties. This has nothing to do with what herbalists (including the purveyors of Chinese medicine) practice. Their prescriptions are based on medieval worldviews, and is entirely unscientific. They prescribe herbs based on their “taste” and “temperament” (which many incorrectly call temperature), not based on their pharmacology. Herbs could be hold, cold, salty, sour, sweet, etc.

    One of the gurus of herbalism in the US is Dan Bensky…

  5. Gaythia says:

    Inorganic chemistry owes quite a bit to the early work of alchemists. Some of these people were early scientists, investigating the properties of what turned out to be chemical elements and discovering their properties, as well as documenting the fact that the ones that were not gold could not be turned into gold. Others were charlatans, using trickery for profit.

    Similarly, I think that indigenous forms of herbal medicine are not “entirely unscientific” even if they currently lack a full scale modern day scientific clinical analysis.

  6. Joe says:

    @Gaythia on 23 Jan 2011 at 10:57 am wrote “… I think that indigenous forms of herbal medicine are not “entirely unscientific” even if they currently lack a full scale modern day scientific clinical analysis.

    I’ll go out on a limb and say yes they are entirely unscientific. Do you have evidence to the contrary?

  7. Anthro says:

    @Joe

    I think Gaythia might mean that some of the things indigenous cultures use plants for may turn out to be effective when they are investigated–at least to some degree. I mean, the hallucinogens that many use DO seem to work.

    I’m weighing in as an anthropologist who is alarmed by my field’s recent proposal to “throw out science”! That is, I am completely committed to respecting and studying every culture’s practices, but not confusing that with acceptance of these practices as scientifically valid.

  8. Gaythia says:

    Joe, I think that all of science has roots in antiquity when someone asked “Why?” and then went scrounging around for actual evidence.

    On pharmacology: David Kroll is the one who should answer this. I’m not the expert. Herbal remedies frequently have, over time and trial and error, given some evidence of success. Willow bark turned out to contain aspirin for example. Thus certainly there are pharmacologists who study herbs used by indigenous cultures in hopes of finding ones that can, by modern clinical analysis, be proven to be safe and effective.

  9. Joe says:

    @Gaythia on 23 Jan 2011 at 10:08 pm

    Actually, willow bark contains salicin as its main analgesic. Aspirin was developed from salicylic acid, also found in willow bark; but originally investigated as derived from salicylic aldehyde found in meadow sweet.

    @Anthro on 23 Jan 2011 at 9:39 pm

    To both of you, yes, several active herbs have been found by ancient peoples. Those are primarily herbs with profound, immediate effects. However, the ancients did not follow the scientific method and they handed down many more tens of thousands of claims that are unsupported by evidence. Their methods also brought us bloodletting, trepanning (drilling a hole in one’s skull), leeches, violent purgatives, etc.

  10. Regarding herbalism and indigenous people. I know very little about pharmacology, so forgive me if this is naive. But, it always seemed to me that if you have a group of people who have been living in an area for hundreds of years, then it is wasteful to ignore their observations of common human reactions to eating, smoking or making teas from local plants. Say a local herbalist says a plant is good for congestion and also will makes the patient sleepy, this might be used as a lead to evaluated that plants sedative or decongestant properties. This, to me, seems superior to just walking into the jungle and testing random plants. On the other hand, I guess that there is a huge field of botanical knowledge that can offer you possibilities based on plant families, common attributes, etc.

  11. Joe – “However, the ancients did not follow the scientific method and they handed down many more tens of thousands of claims that are unsupported by evidence. Their methods also brought us bloodletting, trepanning (drilling a hole in one’s skull), leeches, violent purgatives, etc.”

    Conventional medicine includes bloodletting, purging in it’s history. It also brought us a couple decades (or more) of the prefrontal lobotomy to control difficult people or patients and Electroconvulsive therapy without the consent of the patient. This does not mean that conventional medicine is bad. It does mean that you can’t evaluation the efficiency of a methods by only focusing on it’s mistakes.

    Regarding leeches “Medicinal leeches (Hirudo medicinalis) are a standard treatment for venous congestion, a complication that can occur after reconstructive surgery. If the cause of venous congestion cannot be surgically corrected, then medicinal leeches are used to temporarily increase perfusion levels and maintain physiologic requirements within the congested tissue. Leeches increase perfusion within congested tissue by actively drawing off blood as a bloodmeal. Furthermore, the leech bite continues to bleed and relieve congestion after detachment because of the anticoagulation effects of leech saliva left behind in the bite.”

    http://www.ncbi.nlm.nih.gov/pubmed/11786816

    or search medicinal leeches on med pub.

  12. “Conventional medicine includes bloodletting, purging in it’s history.”

    But “conventional medicine” did not even start to become scientific until the mid-1700s, and science didn’t become a universal standard (even if not universally available or applied) until the mid-1930s.

    The question is not whether herbal remedies could be effective, or even whether they ever are; the question is whether the ancient traditions in which they were embedded are scientific. The answer to the former question is yes; the answer to the latter, no.

  13. Anyway, what Joe said: non-scientific methods can trip over really obvious effects (alcohol, for instance). It takes science to tease out the non-obvious ones and to discard the ineffective.

  14. “Anyway, what Joe said: non-scientific methods can trip over really obvious effects (alcohol, for instance). It takes science to tease out the non-obvious ones and to discard the ineffective.”

    Yes, I agree. But, if we consult the omnipresent Wikipedia, they (a bunch of posters with either a lot of time on their hands or sufficient dedication and knowledge to contribute) define the scientific method as…

    1. Use your experience: Consider the problem and try to make sense of it. Look for previous explanations. If this is a new problem to you, then move to step 2.
    2. Form a conjecture: When nothing else is yet known, try to state an explanation, to someone else, or to your notebook.
    3. Deduce a prediction from that explanation: If you assume 2 is true, what consequences follow?
    4. Test: Look for the opposite of each consequence in order to disprove 2. It is a logical error to seek 3 directly as proof of 2. This error is called affirming the consequent.[9]

    http://en.wikipedia.org/wiki/Scientific_method

    To me, what Gaythia was suggesting would be indicative of the “look for previous explanations” portion of the method.

    Perhaps I wasn’t clear (me? not clear? surprise, surprise) I only wish to say that the observations of indigenous cultures or the ancients, should not be automatically ruled out in looking for previous explanations due to the fact that the didn’t use scientific method.

    Of course, they should not be given a pass on the rest of the scientific process either. :)

  15. “# Alison Cummins
    “But “conventional medicine” did not even start to become scientific until the mid-1700s, and science didn’t become a universal standard (even if not universally available or applied) until the mid-1930s.”

    Just as an aside*, I would speculated the scientific method become the universal standard in 1930 because technology increased enough to make the application of the scientific method more trustworthy and efficient. So, is the issue that some cultures were not using the scientific method (do we know they are not using the scientific method or something similar or are just assuming?) or is the issue that they did not have sufficient technology to effectively support the scientific method?

    *Feel free to ignore this, it might be just my brain spinning.

  16. Scott says:

    The scientific method is a way of thinking – it’s philosophical, not technological. Effective scientific study of an herb’s effects (for instance) may be conducted without technological means.

    So in principle “traditional knowledge” could be scientific, but I’ve not seen any evidence to suggest that it was. And it’s a pretty profound philosophical shift from what humans generally find natural, so it seems quite reasonable to presume that it was not in use in the absence of evidence to the contrary.

  17. Scott says:

    Another point just occurred to me, apologies for the double post.

    A key requirement for effective science is an understanding and use of statistics. So cultures that didn’t do math at that level couldn’t possibly have done science.

  18. scott “The scientific method is a way of thinking – it’s philosophical, not technological. Effective scientific study of an herb’s effects (for instance) may be conducted without technological means.”

    Scott, I’m not sure that I understand this. If you were going to test an herb for it’s anti-viral attributes, wouldn’t it be more effective and reliable to do it with today’s technology rather than the technology of 200 years ago?

  19. “I would speculated the scientific method become the universal standard in 1930 because technology increased enough to make the application of the scientific method more trustworthy and efficient.”

    Nope. Hospitals have existed for centuries, and bloodletting as a treatment for fever had been happening in them until the 1930s. It would have been perfectly scientific and perfectly feasible to make notes of how many feverish people treated with bloodletting got better vs how many feverish people not treated with bloodletting got better.

    Nobody bothered until the late 1800s.

  20. I got this stuff about the absence of science in medicine (US medicine in particular: German medicine was apparently way ahead of the game) from the book Harriet Hall reviewed here:
    http://www.sciencebasedmedicine.org/?p=9275

    http://www.amazon.com/Great-Influenza-deadliest-pandemic-history/dp/0143036491/ref=sr_1_1?ie=UTF8&qid=1293236005&sr=8-1

    Highly recommended.

  21. Also Scott – “And it’s a pretty profound philosophical shift from what humans generally find natural, so it seems quite reasonable to presume that it was not in use in the absence of evidence to the contrary.”

    But isn’t that similar to how Newton (That guy who’s alchemist experiments brought us new ideas on color, light and the visible spectrum) viewed Gottfried Wilhelm Leibniz’s claim to have developed calculus.

    Meaning, most advances are a pretty profound shift, but it does not automatically follow that those pretty profound shifts are not duplicated by multiple individuals or civilizations.

    Also, are multiple posts poor netiquette? If so, I owe everyone a big apology.

  22. Gaythia says:

    I strongly support modern scientific methods. But I don’t think that science emerged out of a void in the 1700′s either. Nor would some of what was taken as scientific medicine in the 1930′s be accepted today. And tomorrow’s discoveries will undoubtedly enhance what is known currently. Our understanding of science has evolved and improved over time. I’m not going to base my medical care on what was thought to be true in antiquity any more than I am going to waste time trying to turn base metals into gold. I still can recognize the roots of the science I know today in those ancient efforts and attempts.

    So I think that there is really no real disagreement here, and we are mostly arguing for the sake of argument.

    How best do we promote what David Kroll describes above as a “lesson of the value of natural products in the identification of new cellular targets”

    Way back at the first comment, Kimball Atwood brings up an interesting point regarding the politics of natural products medical research. What do we do to promote the advancement of scientific medicine? How do we combat those who reject knowledge that is at our current peak of understanding and want to reach back in time and utilize methods currently that are based in antiquity?

  23. Scott says:

    Scott, I’m not sure that I understand this. If you were going to test an herb for it’s anti-viral attributes, wouldn’t it be more effective and reliable to do it with today’s technology rather than the technology of 200 years ago?

    It’d make it easier, but wouldn’t be necessary. One can round up a suitable number of people, provide them with the (randomized) remedy or placebo, track their progress, and perform statistical comparisons of those results without any advanced technology.

    Meaning, most advances are a pretty profound shift, but it does not automatically follow that those pretty profound shifts are not duplicated by multiple individuals or civilizations.

    Entirely true, but the scientific method is far more profound than calculus – it’s the sort of thing that will leave major footprints. They COULD have, certainly, and I’m not willing to rule out entirely that some ancient cultures MIGHT have (largely due to a lack of anthropological expertise on my part), but it’s something that could/would be known.

    Also, are multiple posts poor netiquette? If so, I owe everyone a big apology.

    It’s typically considered so, though different sites differ on how big a deal it is among that community. Sometimes it’s even a banning offense.

  24. Jan Willem Nienhuys says:

    @ Alison Cummins on 24 Jan 2011 at 12:20 pm

    On bloodletting:
    “Nobody bothered until the late 1800s.”

    See:
    http://www.answers.com/topic/pierre-charles-alexandre-louis\and
    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1120016/
    Louis was the founder of the méthode numérique (which inspired Semmelweis) and he criticized bloodletting already in 1835. The insights of Louis were only slowly accepted, but ‘nobody bothered’ until the late 1800s seems a bit too strong. Some famous contemporaries of Louis were also sceptical about bloodletting.

  25. Jan Willem Nienhuys,

    I think I must have been thinking of Louis, so I was off by 50 years.

    According to wikipedia.org, hospitals and outpatient clinics have been around for over 2000 years and bloodletting has been in use for about as long. In that context, that the error is just ±50 years just makes my point: the scientific method in medicine is a modern approach that does not require modern technology to be applied.

    A similar anecdote about foxglove and William Withering http://www.rcpe.ac.uk/journal/issue/vol31_no1/S_Withering.pdf :

    “The plant Digitalis had been known and used in medicine for centuries. Classic descriptions were given both by Dioscorides and Galen. Leonard Fuchs named the plant Digitalis in his book Historia stirpem in 1542 and recommended it for the scattering of dropsy. Withering knew of Fuchs’ work but encountered the plant again when he met a ‘wise woman’ in Shropshire who used the foxglove as one component of her medicine for the dropsy. The concoction contained at least 20 different herbs but Withering states ‘it was not difficult for one conversant in these subjects to perceive that the active herb could be no other than the Foxglove’. Withering’s colleague, Dr John Ash, had also used it for the Principal of Brazen Nose College, Oxford, who had hydrops pectoris. Further evidence came from the work of Mr Saunders, an apothecary, of Stourbridge in Worcestershire, who was also employing it regularly in the treatment of dropsy.

    Withering’s specific contribution was to place Digitalis on a proper scientific footing, and thereby eliminate much of its folklore and superstition. He established that the dried powdered leaf of the plant was five times as effective as the fresh leaf. The powder was also better than a decoction, as boiling seemed to destroy some of the active principle. He then went on to study 163 patients with dropsy, and recorded his results carefully.

    From this protracted study he realised, for the first time, the paramount importance of dose, and also that a brisk diuresis of several quarts of urine often heralded the patient’s recovery. Also for the first time, he described clearly the important side-effects of Digitalis which included nausea, vomiting, diarrhoea and green/yellow vision. The onset of side-effects should lead to an intermission of dose followed by restarting at a lower level. Some patients who appeared similar in clinical presentation did not respond to Digitalis, for example those with tight ascites (who may have had cirrhosis), hydrocele and unilateral dropsy (who may have had post-phlebitic leg).”

    So foxglove had been used as a herbal treatment — at least some of the time for edema — for at least 1700 years by the time Witherington published his treatise in 1785. But he was the only one to have quantified the dose or to make note of what parts of the plant were most potent or what it treated effectively and what it didn’t. This didn’t require modern technology; it only required modern thinking.

  26. Joe says:

    Wow, so many interesting comments. Sorry, I won’t keep track of who said what.

    Digitalis (foxglove) is an interesting example because it was the only one of about 20 ingredients in a folk cure for dropsy (edema, water retention). So, the folk remedy was 95% ineffective. They had an effective product; but did not distinguish it from the junk.

    Similarly, more than 100 herbs were used to treat malaria in ancient China http://www.ncbi.nlm.nih.gov/pubmed/16722826?ordinalpos=21&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum but only one was found to be active in proper tests. Yes, as observed above, it would be a shame to ignore folk wisdom; but (except for dramatic, immediate effects) it is largely in error.

    Another problem with folk lore is determining what a product is used for. First, herbs usually have multiple recommended uses. Then, one must decode the folk description of the malady. There generally are no folk identifications for prostate hyperplasia (the symptoms may have been recorded; but the diagnosis can only be inferred) or hypertension. Also, taxol is currently used to treat cancers that were probably not known in the old days, let alone treated with it.

    It is only recently that we have realized that the only proper test of a drug (which an active herb is) is randomized, blinded, placebo-controlled research. The pre-scientific ancients did not do such research.

    Another problem I have with folk medicine is illustrated thus- suppose tinselweed was used to treat gout, yet it fails scientific testing; do we not test it against other problems (possibly unknown to the ancients)? Taxol is an example of the value of random screening of natural products outside their historic use.

  27. Well drat, I feel like I just found out that nice scented liquid in the lovely bowl on the table is for finger tip rinsing, not drinking.

    My apologies, all.

  28. “But he was the only one to have quantified the dose or to make note of what parts of the plant were most potent or what it treated effectively and what it didn’t. This didn’t require modern technology; it only required modern thinking.”

    So why do we use all that expensive technology, if it’s not necessary for advancing scientific knowledge?

  29. It’s for advancing scientific knowledge further!

    From the William Withering article quoted above: http://www.rcpe.ac.uk/journal/issue/vol31_no1/S_Withering.pdf

    He had no clear idea how the drug worked to ‘scatter’ the dropsy but he suspected that the diuresis it produced might play a part. He also thought that it might improve ‘tumultuous action of the heart’ (which was probably atrial fibrillation) but did not make a clear connection between the heart, dropsy and fluid retention. As a result of these uncertainties, other physicians were to use Digitalis inappropriately, in too large a dose or in conditions where it was ineffective. These problems could not be resolved for a further 100 years until histopathology and electrocardiography became established. Nevertheless, the Treatise on the foxglove was a notable advance based entirely on careful clinical observation and it changed the face of medical practice forever.

    Thus technology and technique are an important part of today’s advanced medical science, but way back when people had the technical means to conduct good preliminary science… but didn’t.

    It’s like the story of Galileo and the bricks. Aristotle wrote that heavier objects fell faster than lighter objects. Over 1,950 years later, Galileo dropped a big brick and a smaller brick off the leaning tower of Pisa to establish that Aristotle was wrong: they landed at the same time.

    Aristotle didn’t have the leaning tower of Pisa, but that wasn’t the limiting factor preventing him from testing his postulate. The scientific method was the limiting factor. It was a way of thinking that hadn’t been developed yet.

  30. Scott says:

    It also makes things a lot easier. Sure, one COULD track and analyze the results of a 500-person drug trial on paper, but it’s a whole lot faster to use a computer.

    Another example would be making sure that your subjects have the same condition. Suppose you’re investigating a bacterial illness; being able to grow cultures and look at them under a microscope (or what have you) means that you can be sure they all have bacterial pneumonia instead of viral (for instance). That makes a trial of antibiotic treatment for said condition give much clearer results. I could take a bunch of people with pneumonia SYMPTOMS and treat them, but if they’re a mix of different underlying conditions it’ll be a lot harder to tell whether what I’m doing is really working for some of them. Could still be done with enough numbers, though.

  31. Joe says:

    @micheleinmichigan on 24 Jan 2011 at 4:04 pm asked “So why do we use all that expensive technology, if it’s not necessary for advancing scientific knowledge?”

    Usually, the modern science is necessary. Withering was working with something (Foxglove, digitalis) that had an immediate, objective result. Advanced technology is necessary to separate the wheat from the chaff when the result is not so clear. When penicillin was introduced, many reports found it a panacea; science showed it had a limited activity.

  32. Joe says:

    I don’t know how I screwed that, it should have been @micheleinmichigan on 24 Jan 2011 at 4:04 pm

  33. “Aristotle didn’t have the leaning tower of Pisa, but that wasn’t the limiting factor preventing him from testing his postulate. The scientific method was the limiting factor. It was a way of thinking that hadn’t been developed yet.”

    Yes, I think I am getting your meaning. But I continue to wonder if a civilization might develop a process similar to the scientific method and yet have diminished or unreliable results due to the lack of adequate technology.

    So my question is notcan you think of historical examples where a discovery was made purely through scientific method without any advanced technology. It is more, can you think of examples where another civilization was not able to adequately test a hypothesis (using the scientific method) without more advanced technology then they currently had?

    If I can think of an adequate example I will share, but I haven’t come up with one yet. My medical history* (like my dissection history) is sketchy. :)

    *Oh, let’s admit it, my history, in general, is not what it should be.

  34. Oh wait (sorry about this a couple posts came up while I was typing my previous comment).

    Scott “Suppose you’re investigating a bacterial illness; being able to grow cultures and look at them under a microscope (or what have you) means that you can be sure they all have bacterial pneumonia instead of viral (for instance). That makes a trial of antibiotic treatment for said condition give much clearer results. I could take a bunch of people with pneumonia SYMPTOMS and treat them, but if they’re a mix of different underlying conditions it’ll be a lot harder to tell whether what I’m doing is really working for some of them. Could still be done with enough numbers, though.”

    and Joe “Advanced technology is necessary to separate the wheat from the chaff when the result is not so clear.”

    These are the examples I’m looking for, which could suggest that is some cases scientific exploration could fail due to lack of technology. Of course, in other cases it can fail due to lack of the process (scientific method).

    I guess that is all I was getting at. Perhaps a long way around the block to get there. But it was interesting for me. :)

  35. micheleinmichigan,

    You’re asking whether technology has ever been a limiting factor? Yes, it has been and continues to be. In the example of Withering, he took digitalis therapy as far as he could, but it wasn’t for another hundred years that science and technology had developed enough to take digitalis therapy further.

    Or are you specifically looking for something cross-cultural?

  36. Scott says:

    Oh sure, that’s easy. It took building the LHC to be able to test for the existence of the Higgs boson.

    Of course, if the US hadn’t welshed on its commitments to the rest of the world by killing the SCSC, that would have done it years ago. But the principle still holds; it took bigger and better accelerators (i.e. more advanced technology) than were available at the time.

  37. wertys says:

    I predict that there will be a huge round of confected outrage when thalidomide makes its comeback as a pain management drug. A whole branch of research is looking at the role of spinal cord cytokines in the transition from acute to chronic pain, and the leading candidate for clinical use is currently thalidomide, which is a potent inhibitor of the cytokines which seem to be largely responsible for the creation of chronic pain.
    See for example
    http://www.ncbi.nlm.nih.gov/pubmed/17367589

  38. Gaythia says:

    @Scott, in a manner that makes less of a “beeline” between funding and anticipated results than your SCSC example, David Kroll’s topic for this post: “new life would not have come to nitroxoline had not a fungal natural product called fumagillin been studied as an antiangiogenic anticancer drug – one that inhibits the formation of new blood vessels.” shows not only “the value of natural products in the identification of new cellular targets”, but also the need for a lot of scientific advancements and diligence in seemingly completely unrelated efforts in areas of biochemistry and pharmacology.

    Things we all need to keep in mind, and help the public to understand, as the government struggles with science funding.

  39. Gaythia says:

    Do you see targeted political de-funding efforts along the lines of this:
    http://www.centerforinquiry.net/blogs/entry/re/

    as having a negative effect on agencies such as NCCAM going forward, and if so, what do you think can be done to promote science?

  40. DJ says:

    I just came across Dr. Kroll’s article and read the responses. I would like to join in with my opinion but with a prior commitment I would not be able to respond until tomorrow. Would appreciate if everybody check back for new responses tomorrow. Thanks.

  41. DJ says:

    Okay, I am free now and so I will upload my comments. I apologize for the length (but not the content) and will split it into two consecutive postings. Any links I include may need to be copy and paste to your web browser but believe me they are worth it. I thank you all for your patience.

    First off I like to thank and congratulate Dr. Kroll for this article not just for the technical information contained therein but for thinking outside the box in the first place. The responses here have touched on several aspects of medicine but unfortunately has degenerated into a battle between giving credit to herbal medicine of early civilizations (Gaythia, Anthro and Alison Cumins et al) and Joe asserting that the old remedies were not scientifically tested and for this and this reason alone there is no merit to their claims at all and dismissed them altogether. It appears that Joe came to the conclusion that the ancients had not done “scientific” studies and experiments because the same combination of the herb(s) used are ofter for 20 different ailments. I must point out to Joe that “scientific study” is relative. Joe has no idea the route these herbal cures had or had not gone through pseudo- or quasi- study but for sure not a randomized double blind cross over control study we employ today. I can guarantee though that there was certainly a lot of try and error and observation and recording that went on. Try and error, observation and recording of results are important parts of scientific studies even today and ofter is the very foundation of how a “modern” scientific randomized double blind experiment or study is formulated in the first place. I would even venture to say that observation is both the first and last in any study, scientific or otherwise. The ancients do not have all the tools and techniques we “moderns” have and so their “scientific proof” is lacking, but that does not make their observation obsolete or invalid nor that there was no scientific study being done to come to their conclusion albeit the very term “scientific” was non-existant at the time but study they did. Currently a lot of effort is spent in deciphering just what within these old herbal remedies are the “active ingredients” and often these natural remedies has no or much less side effects than the laboratory-syntherized chemicals the pharmaceutical companies come up with. (More to this in my follow-up post.) If a certain herbal mix is used for 20 different ailments it was probably because some of the ingredients in the mix were effective against one ailment while others effective against another ailment and the interaction of some of these ingredients are effective against yet other ailments. Joe has decided to throw the baby out along with the bath water. This may be a case of arrogance rather than ignorance, but definite a close mind. I can name you quite a few modern medicines that has multiple used to treat multiple ailments but you don’t seem to reject them for it.

    This reminds me of western medicine dismissing acupuncture not that many years ago simply because they do not understand how it works and their “modern and scientific experiment” is inept to explain it. True, the Chinese practitioners can’t explain how it works either other than that it does work. China and other oriental cultures had been using it for centuries. In our modern society we have lots of drugs that we still have no idea how it works, why it works and the mechanism of it other than it works. Even Joe, who may have absolutely no idea about how and why acupuncture works personally has to admit that today western medicine, YOUR western and “modern” and “scientific” can-do-no-wrong medicine, has embrace both acupuncture and acupressure. (By the way if anybody prone to charley horse of the calf muscle wants to know how to stop it instantly and no pain or limping the next day let me know. It is a pressure point I discovered – without any scientific experiment but it works.) In other instances “ignorance is bliss” may have its place but in medicine and especially cancer treatments and prevention, ignorance and a close mind is the enemy. Progress comes from standing on the shoulders of those before us and not necessarily that of “giants”; some of these shoulders may well be that of a bushman or a primitive herbal practitioner. Progress usually come in small steps and only once in a while a giant leap forward and thinking outside the box is the key.

  42. DJ says:

    (Cont.)

    In recent years there have been a lot of effort spent in deciphering just what within these old herbal remedies the “active ingredients” are and often these natural remedies has no or much less side effects. What I like to see is a marriage between Conventional Medicine with what is often referred to as “Alternative Treatments or Medicine”. I detest the term “alternative” because it implies a mutually exclusive treatment stance whereas many natural herbs are supportive of chemical or radiation treatments or minimize their side effects when used conjunctively. The term I like is Holistic Medicine. Reminds me of the saying: The mind like a parachute functions only when open.

    Case in point, my own experience with my own doctor. He checked and told me that my cholesterol was too high (201) and quickly prescribe a statin (Vytorin). No discussion or investigation as to WHY my cholesterol was too high. I did some research and did not like the risk-reward equation and stopped after a few months. A year after he insisted that I go back on statin and this time prescribes Crestol (he took part in a drug company-funded study of Crestol in the mean time). I insisted on a followup blood test and found my T.G.O. and T.G.P. had shot sky high while my cholesterol dropped to 140 and my other adrenal hormones have dropped to a point that I was in a hypo-adrenal state. My testosterone dropped 4 points in this one month. I had done a lot of research on statins, took Coenzymn Q-10 on my own and of course I immediately stopped taking my the Crestol. There was never any attempt to check the reason for my high cholesterol. Hypothyroid or even subclinical hypothyroid can cause an elevated cholesterol among many other causes. As well, a cholesterol level of 140 is pathologically low; the low limit should be 160 but nobody talks about it. See http://strokedoc.typepad.com/stroke_doc/2006/04/low_cholesterol.html
    and http://archives.cnn.com/2000/HEALTH/men/06/30/low.cholesterol.wmd/index.html#r
    and
    Science News, April 22, 1989 by Kathy A. Fackelmann: http://findarticles.com/p/articles/mi_m1200/is_n16_v135/ai_7551979/?tag=content;col1
    Supportive evidence in the Western World came 6 years after in the NEW ENGLAND JOURNAL OF MEDICINE where scientists found a sixfold greater threat of death from cerebral hemorrhage in middleaged American men with total serum cholesterol levels lower than 160 mg/dl and elevated blood pressure above 90 mm mercury diastolic. The inverse relationship between cholesterol and hemorrhage disappeared for people with normal blood pressure and for those with cholesterol levels above 160 mg/dl.

    Meanwhile policosanol, a natural extract of plant waxes of a group of 8 to 9 long chain alcohols, has been demonstrated (as in “scientifically proven”) to be as good as and in some cases better than three leading statins (Mevacor/lovastatin, Zocor/simvastatin and Pravachol/pravastatin) with no side effects. See Crespo N et al. Int J Pharm Res 1999; XIX(4): 117-127; Ortensi G et al. Curr Ther Res 1997; 58(6): 390-401 and Castano G et al. Int J Clin Pharm Res 1999; XIX(4): 105-116 respectively.

    I am not trying to turn this into a statin forum and indeed there are instances where statin is indicated and extremely useful in the TREATMENT of cardiovascular diseases. Statins had been suggested to be use in pre-transplantation instances due to statin’s ability (side effect actually) to suppress the immune system. Why would anyone take statin to prevent cardiovascular disease and lower his immune system or risk a hemorrhagic stoke (the worst kind of stroke) when one should be checking out the cause of the high cholesterol in the first place, diet and exercise, vitamin and supplements and take policosanol if needed.

    Funding for research is another hurdle that researchers has to contend with. Unfortunately pharmaceutical companies would not give grants for research to natural products because they cannot patent them. Even if they do they would keep the results a secret while trying to make a similar chemical and hope for similar effect so they can patent and sell their product. Think back to the old hormone replacement days compared with now the identical hormone replacement pioneered by Dr. Jonathan Wright. I understand the pharmaceutical company’s position. They are first and foremost a business albeit a health-promoting business. Check out this link: http://www.youtube.com/watch?v=HVTaJn1dMrs&NR=1 and http://www.youtube.com/watch?v=EtjvbE9w58A&feature and http://alternativecancer.us/testr.htm .

    If we are open minded, think outside the box, be responsible for our own health (lift style changes as in diet, exercise, etc.), not arrogant and treat the disease by looking for the cause instead of a life time of pills to suppress the symptom until we drop, our medical costa will be much lowered and we all will have a better health for it. There need to be a system of grants set up for natural product testing where there will not be a patent but will benefit medicine. The cost of the research compare to the cost of treatment with chemicals made in the lab would be well worth it. A marriage of all aspects of medicine, traditional and natural medicine leading to a holistic approach will give us the lowest cost and truly the biggest bang for the buck (not a political talk).

  43. “The responses here have touched on several aspects of medicine but unfortunately has degenerated into a battle between giving credit to herbal medicine of early civilizations”

    ?

    I wouldn’t even start to consider that a discussion had degenerated on SBM unless it hits at least 100 comments, is on a completely different topic than the orginal article or someone’s been called a troll. Even then, I’m not sure that a degenerated discussion would always be a bad thing (with the exception of the afore mentioned troll accusations). Everything else is just a friendly exchange of ideas.

  44. Joe says:

    @DJ on 29 Jan 2011 at 10:00 pm wrote “… Joe assert[ed] that the old remedies were not scientifically tested and for this and this reason alone there is no merit to their claims at all and dismissed them altogether.”

    No, you have offered a straw man (an argument that I never made, which is easily attacked). I acknowledge that several herbs with immediate and dramatic effects were identified (e.g., cinchona, foxglove, hallucinogens, willow bark, …). I gave the example of only one anti-malarial herb out of more than 100 in ancient Chinese cures being effective. That is what you get from trial and error (along with trepanning (drilling holes in the head), violent purgatives and bloodletting). The evidence is that trial and error fails. After we learned that, we adopted the scientific method because it is less prone to error and it is self-correcting when mistakes are made.

    In your subsequent post, you offered old research on policosanol- if you look at recent publications (on PubMed, limited to human clinical trials- the number is not large) you will find the latest, reliable research finds it is not so clearly useful.

    You also assert that acupuncture is effective. You can read a lot about that on this site- it is no more useful than placebo- which means it is ineffective.

    As for “natural remedies” having fewer side effects. There are two reasons for that 1) they have no more activity than lettuce and 2) nobody is watching for their dangers and long-term hazards go unnoticed.

    Aristolochia is a prime example of what is wrong with traditional herbs. It was used to treat women after childbirth based on the notion of “signatures.” (The flower looks like the “birth canal” (the signature) so it must help.) (Yeah- a lot of your ancient remedies are based on this, not trial and error.) We don’t know how many women died as a result of being given this kidney-killer (yeah it causes kidney failure followed by kidney cancer); the death is not immediate.

    Finally, do you recommend polypharmacy? You note that the 20 herb treatment that had one active ingredient for congestive heart disease was probably used for many conditions. I am interested if you can provide the effect of each ingredient, and why people should take all 20 of them when most complaints are unrelated.

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