May 24, 2015
Imagine A Drug That Improves Many Metabolic Measures

The trick is to know how to stimulate soluble guanylyl cyclase (sGC).

in mice made obese by a high-fat, high-calorie diet, the sCG stimulator not only promoted weight loss, it also improved glucose tolerance, reduced insulin levels and drove down signs of fatty liver -- a damaging consequence of established obesity. It even shrunk white fat cells.

Soluble guanylate cyclase (sGC) is a target of considerable interest in drug development:

The enzyme soluble guanylate cyclase (sGC) is the only known nitric oxide (NO) receptor in the human body. Nitric oxide is formed in the endothelium a thin layer of cells on the inside of blood vessels and plays an important role in the human cardiovascular system.

Nitric oxide activates soluble guanylate cyclase, which in turn initiates the production of the messenger cGMP (cyclic guanosine monophosphate). cGMP causes the smooth muscle cells in the vessel walls to relax (vasodilation), so that the blood pressure falls. In addition the messenger counteracts cramp, thickening of the vessel walls, and the depositing of platelets and connective-tissue cells, which can clog the blood vessels and reduce their elasticity. cGMP also inhibits excessive cell proliferation and inflammation.

Obviously penicillin and the other antibiotics are great drugs (or at least they were until they were so overused that resistant strains of bacteria sprouted up). But since the antibiotics were introduced how many drugs have come along that are really great? Are you taking one? What is it?

I would call a drug great if it could take off weight, improve glucose tolerance, and reverse fatty liver disease.

Share |      Randall Parker, 2015 May 24 06:48 PM 


Comments
bob sykes said at May 27, 2015 4:45 AM:

The so-called "overuse" of antibiotics is an example of biological illiteracy among physicians. Everyone who has taken so much as one course in biology (which apparently does not include medical students) will have heard of Darwin and natural selection.

The direct consequence of natural selection is that any use of antibiotics that is clinically effective will create a selective pressure for drug resisitance among the targeted microbes. Higher rates of usage and dosage will create higher selective pressures, but any effective use creates as selective pressure.

The result is that microbes inevitably become resistant, regardless of usage level, and the drug loses its efficacy. This is Biology 101, or maybe even remedial biology.

The solution is to continually develop new antibiotics and take the old ones off the market. Once a selective pressure is gone the microbes will lose their resistance (because of random mutations), and eventually the drug, penicillin or whatever, can be brought back.

Brett Bellmore said at May 27, 2015 9:39 AM:

Not just biological illiteracy. Physicians don't want to own up to the extent to which they're responsible for antibiotic resistance being a problem.

Transmission between patients at hospitals is largely responsible for multiply resistant strains. Who controls hospitals? Physicians.

Further, there are serious issues with dosing practices, (My wife and I get the same dose of antibiotic when we get resperatory infections. I'm three times her weight!) failure to make any effort to determine even if an infection is bacterial or viral, let alone to culture the infectious agent to see if the prescribed antibiotic will work. You let the patient find that out, when they get sicker instead of recovering.

Medicine is making enormous strides, but the standard of practice seems to be declining.

The autodocs can't come too soon.

ikechi said at May 28, 2015 4:14 AM:

The autodocs can't come too soon.

Ron said at May 28, 2015 11:53 AM:

as a physician, I read in amusement the comments about biologic illiteracy. Obviously, these comments were made by people who have minimal to no knowledge of medicine. First and foremost, they are applying knowledge that was unavailable until the last ten years or so, and then act as if it were a grand conspiracy to sicken the general population. Nice job guys, as the extended effects of the use of antibiotics is only now becoming known. Not just breeding superbugs, but the effect on the microbiome of the gut. But snide comments from no nothings are just that.
Additionally, these comments have never seen the effects of telling a patient that 'they just have a virus' and that antibiotics are useless. I have been berated and belittled by patients to whom any antibiotic validated their illness--even when their sinus discomfort was clearly seasonal allergies. Nor have they talked to the parents of sick children, those sick with the run of the mill viruses that infest all child care centers. To most of them, not giving an antibiotic is tantamount to consigning their child to the morgue.
Epidemiologists have been warning for decades about the indiscriminate use of antibiotics, and a lot of american physicians have agreed and complied. But what these comments don't acknowledge is that in a lot of the rest of the world, antibiotics are over the counter, that people purchase them, take them for a few days, and never take the full course. That, in and of itself, breeds resistance faster than anything. Google metalloprotease producing bacteria......and the absolutely awful future for antibiotics they predict. All of them came from south and southeast asia, where there is no restriction on obtaining antibiotics.

nick said at May 28, 2015 12:23 PM:

RON Says... "First and foremost, they are applying knowledge that was unavailable until the last ten years or so..."

At least 20-25. I recall this being discussed in graduate classes I took with Gold at Berkeley in the early 90's.

Interesting that you contradict yourself by saying that "Epidemiologists have been warning for decades about the indiscriminate use of antibiotics..."

As for blaming parents. When my daughter had pneumonia the doctor patiently explained she just had the flu, and we went away, not disagreeing with her. Two days later I knew she had pneumonia and still I had to fight with my pediatrician. I ended up taking her to the emergency room where they filled her to the gills on antibiotics. And almost made a mistake on dosage (like 10 times the amount) that I caught because I was paying attention.

The problem is that doctors like to think of themselves as godlike. They aren't. Frankly, I wait for the day WATSON supplants most of the first line doctors.

trey said at May 28, 2015 12:42 PM:

Cry me a river, doc. I've never talked to anyone who didn't have a ton of stories about doctors getting annoyed with and refusing to listen to the special circumstances or history of their conditions, and then getting much sicker because of it. I once got antibiotic ear ointment for an ear infection. I complained, as I always either get oral or a shot of antibiotics. I was condescended to and told they were trying to keep down resistance. I ended up 2 days later in the emergency room because I couldn't stand the pain. They told me I had an inner ear infection, and the ointment wouldn't even have reached it. Like I said, I have multiple stories like this as does everyone I know. Now I trust doctors as much as second-rate auto mechanics, and I get my health taken care of much better.

Brett Bellmore said at May 28, 2015 12:44 PM:

"I have been berated and belittled by patients to whom any antibiotic validated their illness--even when their sinus discomfort was clearly seasonal allergies."

And I, at 220 lbs, have been given the same dose "Z-pack" as my 80 lb wife. Usual result being that she'd end up with stomach upset, and drop the antibiotics early, while my pack would run out before the infection was quite over and done, and I'd be sick again within a few days of taking the last dose. Been through that several times, apparently the things only come in one size.

How long ago did we figure out that the proper dose of an antibiotic is a function of body weight? And yet, the standard dose for azithromycin is the same regardless of the patient's size.

Please explain THAT, Mr. Physician.

Sarge said at May 28, 2015 1:56 PM:

Seems like someone ho made it all the way through medical school would have an understanding of the distinction between "no nothing" (a double negative) and "know-nothing" (a pejorative.)

But what would I know about English... I'm just an engineer.

Vince said at May 28, 2015 3:52 PM:

It would be nice if we could have a discussion without regressing into little insults over language use.

Ultimately, it doesn't matter if the problem stems from patients under/incorrectly utilization (common) or from over-prescription by doctors (also common). Functionally, it is the same problem. That said, from my vantage point, I'd rather over-prescribe and over-bias saving/improving quality-of-life than not -- chemical space is enormous (combinatorially enormous) and we can always exploit it better in time with better molecules. We have nice toolsets for this whose improvement scales very nicely with improvements in computing, information sharing and research improvements. Immediate emergence of resistance as is commonly predicted isn't a near-term problem when compared to the dynamic timescale of drug development.

Engineer-Poet said at May 28, 2015 3:59 PM:

Hey, me too!

The last time I had a nasty, long-lasting and worsening respiratory infection (weeks), I went to the doc for antibiotics.  He said it would get better on its own (I went to him because it wasn't).  Two days later I had full-blown pneumonia, coughing up blood.

I wrote him and demanded my co-pay back.

Vince said at May 28, 2015 4:10 PM:

Oh! Returning to the actual question: But since the antibiotics were introduced how many drugs have come along that are really great? Are you taking one? What is it?

First, realize what you're doing Randall, you're drawing analogy between one molecule and asking why any one isn't "great" as compared to a functional class of molecules (antibiotics) which compose many different structures, each with their own targets, idiosyncrasies, promiscuity, benefits, cons, etc.

I would say there are many such classes: Atorvastatin and Crestor is obvious given it's ubiquitous. The PSK9 inhibitors look promising.

What about cancer drugs, like Trastuzumab or recently Crizotinib, etc.

Or the whole suite of HIV drugs? Stribild? Absolutely remarkable progress when you consider the life expectancy in the early days when an unknown illness called "GRID" first emerged to the prognosis of someone who is diagnosed today.

Grumpy said at May 29, 2015 10:22 AM:

LOL you guys are soooooooo much smarter, experienced, and versed in the minutiae of the situation than us dumb old Docs. Someone should really just put you in charge! Because of course, *all* you need to know is that abx induce resistance in bacteria.

The problems in medicine are more complicated if you look beyond a superficial analysis. In medicine, you are *always* dealing with incomplete and oftentimes contradictory information. Are these symptoms viral? Bacterial? Impending pneumonia? Currently we don't have great ways to tell. It is not unusual for a problem to start out as a viral infection and then develop into a bacteria superinfection, and that's not something that's predictable (at least with current technology).

You are also dealing with conflicting values system. A utilitarian values system would lead you to restrict the use of abx as much as possible. However, when you're dealing with a patient you're more focused on trying to optimize care for *that* patient, more of a deontological context. You want to do what's best for the patient. Societal considerations are important, but the patient's welfare is usually foremost in you mind. Most people go into medicine b/c they want to help people, and tend to operate more in a duty based ethical paradigm.

For those that "can't wait" for the advent of autodocs, just be aware that those programs are going to assign a probability to symptoms being viral in nature and base decisions off of that. If you support abx restriction in general, then if you get harmed by antibiotic restriction, it makes no sense to complain. So if you're in the (say) 20% that has a bacterial infection, and you don't get antibiotics, and you get pneumonia, then you don't get to complain about that. It's just too bad, those are the odds.

Finally, although it seems to be intuitive, I'm not aware of any high quality trials (controlled, intention-to-treat) that actually demonstrate that abx restriction (in a clinical setting) reduces induction of resistance in practice. Makes sense that it would of course. Anyone aware of any such high quality clinical evidence?

Engineer-Poet said at May 29, 2015 7:24 PM:

We mere humans know our own medical histories a lot better and have much more time and incentive to dig into symptoms than you do in a 30-minute office visit.  If we haven't seen you in the year since we joined your HMO and suddenly show up with something needing attention, you can be very sure you're not dealing with a hypochondriac either.

Grumpy said at May 29, 2015 7:55 PM:

That's just it. A certain percentage of people that show up requesting abx need them. A certain percentage don't. We don't have a really good way to differentiate. And trust me, E-P, (I'm sure you know this) you are not reflective of the typical patient in level of sophistication or motivation to learn about symptoms and treatment options. Even in your situation, though, where you're willing to be proactive, experience in seeing thousands of different pts in thousands of different situations is valuable.

Even with knowledge and experience, though, you are always operating in an environment with incomplete/contradictory information. It doesn't matter how good an expert system is in that kind of environment. Decisions will get made based on probabilities. When decisions are based on probabilities, sometimes you come up snake eyes.

For what it is worth, I do think many primary care functions can be delt with by an expert system. That's one reason I went into surgery. I expect that surgery too will get taken over by robots, but not in my professional lifetime.

Drclavis said at September 26, 2015 3:27 AM:

The autodocs cant come too soon, it will take time

ziclac said at August 24, 2016 2:23 PM:

I'm not aware of any high quality trials (controlled, intention-to-treat) that actually demonstrate that abx restriction (in a clinical setting) reduces induction of resistance in practice

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