written by reader A Few Things to Keep an Eye On

"Doc Gumshoe" checks in on health and medical news

[ed note: Michael Jorrin, aka “Doc Gumshoe,” is a medical writer (not a doctor) who shares his thoughts with us once or twice a month. As with all our guest authors, his words and opinions are his own]

The stream – or should I say “torrent” – of medical and health-care related news doesn’t seem to be affected by any of the questions of the day, big or little. Will Bangladesh be totally under water by 2100? Will Chelsea Clinton’s baby run for president in 2048? Will we ever again be able to afford to put limes in our gin gimlets? No matter – the medical news keeps coming at us, and Doc Gumshoe tries sort it out with balance and skepticism, employing whatever scraps of sense he can muster.

Let’s start out with this tid-bit…

Can glucosamine supplements give you 8 more years of life?

If so, it could be excellent news for all of us, as well as for the glucosamine supplement manufacturers. The basis for this possibility is a study in which elderly mice were given glucosamine supplements, and in comparison with mice of the same mouse vintage which did not get the supplements, the glucosamine-fed mice lived approximately 10% longer. (Weimer S., Nature Communications, 2014)

Glucosamine, as no doubt lots of you know, is widely used as a supplement for joint pain. Of the currently available forms, only for glucosamine sulfate is there some evidence of effectiveness, and this evidence is not very robust. I personally take glucosamine in the hope that it will help with my creaky knees, and I can’t attest for sure that it does help. What I can say is that for several months I stopped taking it, and during that time I had a sense that my knees got worse, so for whatever that’s worth…

The rationale for glucosamine’s effectiveness in joint pain is that it is a precursor of substances called glycosaminoglycans, which are components of the cartilage providing cushioning and mobility to joints. In other words, glucosamines supposedly help build cartilage. Personally, I hope so!

However, for the mice in the study which is the basis for the claim that glucosamine might grant us an extra 8 years of life, it was certainly not relief of mouse-arthritis that conferred the benefit.

Most of the study did not focus on mice. Instead, it focused on nematodes, which you might know as very small worms. What glucosamine appeared to do in the nematodes is to interfere with glucose metabolism, so that it mimicked the effect of a reduced diet. And in doing so, it increased the life-span of the nematodes.

There wasn’t much in this study about the metabolic effects in mice, but it did report that when two-year-old mice (that’s old in mouse-years) were given glucosamine, most of them survived a bit more than another year, whereas the mice that didn’t get glucosamine survived only about nine months. So that’s where they got the extra 10% life-span, which translated into about 8 extra human years.

The assumption, not stated in the paper, is that the bonus came from the caloric restriction, which is a putative effect of glucosamine. There have already been studies that show that putting mice on severe diets – the equivalent of the diets that Brazilian fashion models follow – does seem to extend mouse life spans (although we have no data on the life-spans of Brazilian fashion models).

A caveat is that there is concern that glucosamine (in large doses) may damage pancreatic islet cells and thus possibly lead to type 2 diabetes. And it is known that people who take glucosamine for joint aches frequently take more than the recommended dose, perhaps upping their diabetes risk. However, there is zero evidence of glucosamine actually causing diabetes.

As for extending human life spans by 8 years (or even 8 months or 8 weeks), we’ll just have to wait and see.

Speaking of mice, a potential Alzheimer’s breakthrough?

No, as far as we know, mice do not develop Alzheimer’s dementia. However, they do develop amyloid beta deposits in their tiny brains, and amyloid beta is what is thought by most researchers to be a principal cause of the typical Alzheimer’s dementia symptoms in humans. Therefore, a Holy Grail in the quest for drugs that may be effective in treating Alzheimer’s disease is some agent that will slow, halt, or even reverse the deposition of amyloid beta plaque in the human brain.

A small digression: the evidence linking amyloid beta and Alzheimer’s dementia is very strong. But there are also bits of confounding evidence, namely that on autopsy the brains of some persons who have exhibited no signs at all of dementia have been found to be thoroughly clogged with amyloid beta, and some individuals who were exceedingly demented in life have been found, on autopsy, to have relatively amyloid-beta-free brains. So there is at least some basis for the theory that dementia and deposition of amyloid beta progress on parallel linked tracks, but the causal link is somewhat less than totally determinative.

A problem hampering Alzheimer’s research has been that good animal models for the investigation of the effect of agents on the formation of amyloid beta have been lacking. When mice develop amyloid beta, they tend to over-express a precursor protein that give rise to a number of effects that are unrelated to Alzheimer’s. They tend to die prematurely, perhaps because the protein may have some toxic fragments as well as some possibly protective fragments, so it is not possible to judge the effects of potential human Alzheimer’s disease drugs in these mice.

To address this deficiency, a group in Japan has manipulated the genes in two subtypes of mice, so that they mimic the human form of Alzheimer’s. These mice could be used to gain greater knowledge of the deposition of amyloid beta, and also to identify early biomarkers for Alzheimer’s dementia. Eventually, they could contribute to the development of the Holy Grail drugs that might actually have an effect on the progression of this disease. If so, we would owe yet another vote of thanks to the mouse tribe.

Might caffeine have a beneficial effect in Alzheimer’s disease?

About three years ago a highly theoretical study was published in the Journal of Alzheimer’s Disease suggesting that caffeine, through its effects as a blocker of adenosine receptors, might have a beneficial effect on the aging process overall, and in particular might delay the progress of Alzheimer’s disease. (Marques S, JAD, 2011) Now, along comes something a bit more concrete.

A French-German group has demonstrated – once again working with those long-suffering mice – that blocking a particular subtype of the adenosine receptor had a marked effect on reducing tau deposits in the brains of the mice that were treated with an agent that blocked the A2A adenosine receptor. (Laurent C, Neurobiology of Aging, 2014) (Tau deposits, along with amyloid beta, are hallmarks of the degenerative process that takes place in the brains of Alzheimer’s patients.)

No, these mice did not get coffee along with their breakfast nibbles. The agent they got was highly purified and did not contain any of the other potentially neuroactive substances that we get in our cup of joe. But the active adenosine receptor blocker was identical to what a lot of us consume daily.

Not only did the caffeine-derived drug reduce their tau deposits, but it had a beneficial cognitive effect, including on “spatial memory,” which I assume means remembering where the cheese is hiding. So, once again, thanks to the mice.

Tumor-necrosis-factor inhibitors, taken for rheumatoid arthritis, also appear to have cardiovascular benefits

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Rheumatoid arthritis (RA) substantially increases the risk of experiencing a range of cardiovascular events, including what are known as “acute coronary syndromes,” which include heart attacks, resting angina, stroke, and other events requiring hospitalization. In some cases, the cardiovascular disease (CVD) rate in patients with RA is as much as twice as high as in persons without RA. There could be multiple reasons behind this link, including the reduced physical activity of RA patients, but the likeliest connection is that RA patients, in addition to being affected in a number of joints, also have systemic inflammation. And inflammation is a major factor in CVD.

Tumor-necrosis-factor inhibitors (TNFi’s) were introduced about fifteen years ago, and they have genuinely transformed the management of RA. Where it was not unusual for an RA patient with aggressive disease to find herself (RA patients are women more often than not) severely crippled within a few years of the earliest symptoms, these disease consequences can now almost always be prevented.

Two studies were presented at the 2013 meeting of the American College of Rheumatology that reported, with a large degree of statistical force, that TNFi’s also reduced the incidence of CVD in RA patients. In one study, (ACR 2013 Abs #804) following more than 30,000 RA patients in Sweden, those on TNFi’s had a 20% reduction in acute coronary syndromes. Another study, (ACR 2013 Abs #2760) this one in nearly 15,000 RA patients in the UK, found that RA patients on TNFi’s had a 40% lower incidence of heart attacks than those not on TNFi’s.

While neither study demonstrated a specific causal link between the TNFi and the cardioprotective effect, the most likely assumption is that the anti-inflammatory activity of the TNFi’s is what resulted in this benefit.

Of course, this in no way suggests that TNFi’s should be used as heart drugs in persons who do not have RA. However, it might serve to offset some patient fears regarding TNFi adverse effects, which, although relatively rare, are nonetheless real.

Doc Gumshoe’s take is that this is definitely Good News.

Can a really old drug make a difference in cancer treatment?

The drug, CBL0102, from Cleveland BioLabs Inc., is, in their words “a quinacrine.” Quinacrine has been around for a really long time. As the name suggests, it is closely related to quinine compounds. It has been used to treat malaria, several protozoal diseases such as giardiasis, some autoimmune diseases such as systemic lupus, and parasitic diseases such as tapeworm. It has quite a lot of side effects – the usual less severe headaches and GI side effects, but also a number of disturbing psychological side effects, and even skin side effects. So it’s not likely to be a top choice in treating early-stage cancers that might be managed successfully by other means.

The mechanism of action of this agent from Cleveland BioLabs is that it affects several intracellular pathways that are commonly disrupted in cancer. It blocks the activity of the chromatin remodeling complex. This complex deregulates signal transduction pathways, including p53 (a tumor suppression protein), heat-shock-response proteins (which among other things protect cells from cancer), and a protein designated as NF-kB. Incorrect regulation of NF-kB is involved in several inflammatory and autoimmune diseases, septic shock, and also cancer. So attacking the chromatin remodeling complex appears to be a good thing.

A study evaluating CBL0102 was conducted at the Russian Oncological Scientific Center in Moscow. Thirty-two patients with advanced cancers which had not responded to conventional therapies were enrolled. All primary and secondary objectives of the study were met. Some individual results of note included a 46% reduction in the tumor of an advanced breast cancer patient, disease stabilization in four other patients, and long-term stabilization in a patient with liver cancer.

Of course, none of this remotely approaches what could be considered a “cure for cancer.” But it suggests a possibly promising avenue. Cleveland BioLabs has in development another agent, CBL0137, which also addresses the chromatin remodeling complex. And another study in CBL0102 was recently initiated in cooperation with the National Cancer Institute.

As Doc Gumshoe has said before, clinical trials in cancer are about as difficult as it gets. No trial with an untested agent is conceivably going to enroll early-stage patients for whom other treatment options exist, so the patient population is going to consist of “hopeless cases.” So when there’s a glimmer of hope with the hopeless cases, there’s real cause for optimism.

Another cause for optimism with regard to this agent is that it addresses a part of the disease process that is common to all or most cancers. It does not require tailoring a specific therapy to the patient’s genome. It’s a simple molecule, and it might just work.

Beating up on Zohydro ER

Zohydro ER is an extended release formulation of the painkiller hydrocodone, containing 50 mg of hydrocodone in each pill. It was approved by the FDA on 25 October 2013, overriding the recommendation of an advisory panel that had voted against the approval of Zohydro ER in December of 2012, based on what they considered to be its potential for abuse.

Zohydro differs from the other formulations containing hydrocodone, such as Vicodin and Lortab, in two major respects. From the standpoint of patients experiencing constant chronic pain, it is a long-acting drug, and is effective for about 12 hours, in contrast with the other short-acting drugs, which may need to be taken as often as every 2 hours. And it is not formulated containing acetaminophen (Tylenol), which is compounded with hydrocodone in most other opioid painkillers.

Opposition to Zohydro ER is vigorous, vocal, and widespread. The greatest publicity went to the proposed ban on Zohydro ER by Governor Deval Patrick of the Commonwealth of Massachusetts. However, this ban was struck down when the manufacturer of Zohydro, a pharm outfit called Zogenix, brought suit in Federal court. (Zogenix is a small firm in San Diego, market cap about $250 million. It’s only other product to date is Sumavel, a self-injection delivery vehicle for the anti-migraine medication sumatriptan, which they have sold to Endo; however, Zogenix is working on two abuse-deterrent formulations of hydrocodone.)

In addition to Massachusetts, however, attorney generals in another 20 states have joined in, asking the FDA to rescind the approval of Zohydro.

There’s no doubt that their grounds for fearing the addiction potential of this drug are real. Each pill contains 50 mg of hydrocodone, and the pills can be ground up and either snorted or injected, so that instead of producing a gradual, low-key narcotic effect, the whole effect of the active drug is felt immediately. Arguing in favor of banning Zohydro ER, advocates point out that of the nearly 40,000 drug overdose deaths in the US, about half are due to prescription painkillers, and about ten times that number wind up in emergency departments every year.

Opposing the ban are those arguing in favor of continuing to make Zohydro ER available to patients who need effective pain medications that have a longer duration of action. Undertreatment of pain is a reality in US medical practice, if for no other reason than that many physicians may be over-careful in prescribing the most effective painkillers. The result is that patients simply live with the chronic pain, which limits their capacity to work and live normal lives.

Specialists in pain management cite a range of figures for the number of Americans who experience chronic pain. As many as 47% of American adults may experience some type of chronic pain, of varying intensity, and at various body sites. This huge number, 100 million or higher, is in no way representative of the number of persons in need of a painkiller such as Zohydro, but the potential patient base for such a drug is certainly quite large, possibly several million.

Most pain experts think that the risk of addiction in patients who genuinely take opioids for pain relief is relatively small. But once the drugs are in medicine cabinets and pharmacy shelves, the potential for abuse is inevitably present.

One of the measures used by many pharmaceutical companies to attempt to limit abuse and addiction is to compound the opioid with acetaminophen. This has two distinct effects. Since acetaminophen is an analgesic, it’s possible (at least theoretically) to achieve the same pain relief with a somewhat lower dose of the opioid. And, because acetaminophen also acts as a blocker of cannabinoid receptors, it tends to lessen the narcotic effects (but not the analgesic effects) of the opioid (note, interactions between opioid and cannabinoid receptors have been well documented). In other words, hydrocodone plus acetaminophen doesn’t work quite as well as a recreational drug as hydrocodone alone.

So far so good. The problems come when the addicts overdose. If one Vicodin doesn’t do the trick, take more! And take more after that, lots more! When addicts overdose on the hydrocodone component and wind up in the ER, procedures exist that reverse the effect of the opioid pretty quickly without much permanent harm, and some EMT personnel carry agents that are effective in dealing with opioid overdoses.

Not so with the acetaminophen. The bad effects from acetaminophen overdosing manifest gradually. And they are largely irreversible. The FDA limits the amount of acetaminophen that can be compounded with a single dose of opioid at 325 mg, but there’s nothing to stop the addict from taking enough doses to amount to a really dangerous acetaminophen overdose. (Note, lots of people know about the dangers of high-doses of acetaminophen accompanied by alcohol – what they may not know is that too much acetaminophen by itself is extremely dangerous – 4000 mg in 24 hours is a dangerous overdose and more than 7000 mg can be fatal.)

The harm done by acetaminophen overdosing is to the liver. It is estimated that about one-half of all the liver transplants due to acetaminophen overdosing are due to acetaminophen taken with hydrocodone, not to the Tylenol in our medicine cabinets. Thus, abuse of the painkiller preparations specifically compounded to mitigate abuse is what results in those liver failures.

Viewed in that light, a hydrocodone-only extended release preparation would seem to make a lot of sense. There are certainly patients whose pain is intense enough to need an opioid, and for whom taking a tablet every two hours is more than an inconvenience – it becomes a serious impediment to normal life.

Prevention of drug abuse is no doubt an important concern for law-makers and enforcers, but the best interests of patients in severe or chronic pain might not be at the top of their priority list. I would suggest that they turn their attention to the so-called “one-stop pain clinics” in some states that prescribe and dispense opioids to busloads of “patients,” who present themselves, claim to be in acute pain, get a prescription from a doctor on the premises, and depart with several months supply of a drug which they go back and sell on the street. At the very least, those should be shut down.

A final note on this subject: Purdue Pharma, the maker of OxyContin, is developing an “abuse-resistant” formulation of hydrocodone. The abuse-resistant feature is that the tablet cannot be ground up, therefore it cannot be snorted or injected. It can only be taken intact, which means that the quick high just won’t happen. When this formulation gets to the market, my guess is that most docs will prescribe it in preference to Zohydro.

* * * * * * *
I didn’t get to half the interesting items on my agenda. Among those still to come – the promise of metallopolymers to boost the efficacy of antibiotics against resistant bugs, and the use of nanoparticles to enhance delivery of cancer drugs. Readers of Doc Gumshoe’s little pieces have asked for comment on quite a range of subjects, such as the merits of a gluten-free diet, the causes and management of vertigo, and many others. Do please let me know what you’re interested in reading about and I will try to train my antennae on those topics. Thanks to all, Michael Jorrin (aka Doc Gumshoe)



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June 6, 2014 6:05 pm

Hey Doc..
Really good, real-world, helpful stuff you have for us here. The comments on glucosamine answered a couple questions I have long held about the products. I tried it. Couldn’t tell it made any difference to anything except the weight of my wallet.
Of most interest for me were your comments on Zohydro. I wasn’t aware of the dangers inherent in the acetaminophen that is in the Oxy products. I thought that was just a “filler” of sorts with a small pain-relieving side benefit. Now I know better, thanks to you. I have never had a pain management specialist or GP explain this to me in any way. This is critical understanding to have.. I hope the Zohydro can get past the legal challenges it faces. People will always find a way to abuse any substance if so inclined. But the vast majority that will not, who use these things as prescribed to try and live a more normal life are punished. I cry FOUL! I can tell you what would change the minds of those 20 Governors; have them herniate three or so lower back discs and feel the pain. Live without help for a couple months. Then see how fast they would drop those lawsuits and get to the doc for a Rx of their own. Some things we can only truly understand through actual personal experience, not just reading a report about it.
Thanks for the info, Doc. Really helpful stuff! Keep ‘um coming!
Maybe a comment on some supplements like the neuropathy support formulations that contain Vitamin B1 and B12 as well as Lipoic Acid. I use one of those and it seems to have helped reduce foot pain and cramping quite a bit. Or is that just my imagination?
Jim Skelton
The Blind Squirrel

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