The ginger paradox

For odd reasons I was looking for papers on orlistat, in particular for rodent papers about the drug which might demonstrate effects relevant to the Protons/ROS hypothesis.

Rodent reports seem to divide up in to those which use an intermittent oral dosing regime vs those which incorporate the drug in to food as a fixed component of the ration. It became clear that if you mix orlistat with the ration you can exactly titrate the amount of lipase inhibitor to the dose of fat administered and include this with every meal and every snack, whatever the size and whenever consumed. This latter has no bearing on the real life use of the drug where it is given three times daily to establish a background inhibition of enteric lipases and people have to judge their fat intake in relation to how far they are from the nearest toilet and if they are carrying spare underwear. Not the most successful or pleasant drug for weight loss per unit grief and it doesn't seem to work very well.

Of course unpredictable bowel function doesn't matter to a lab rat, it's not wearing underwear and it can pooh whenever it likes, wherever it likes because it lives in a mesh floored cage.

There is remarkably little in the rodent literature on orlistat alone for obesity control and mostly you have to look at drug or supplement trials where orlistat was used as the control/usual care group. In these trials it is usual to use intermittent oral dosing rather than admixture to the food because intermittent oral dosing doesn't work very well. If you have an ineffective but conventionally accepted drug that then provides an ideal comparator to show your intervention does something good.

Aside: Just think of metaclopramide. It was/is a standard antinausea/antiemetic for post op use. It is ineffective, dreadful stuff but it's licensed. Which makes it ideal as a "standard therapy" against which to compare a lovely modern drug such as maropitant or ondansetron. You know the latter are going to beat metaclopramide  hands down because metaclopramide is little better than placebo and makes you feel crap. Study design is important and this shows in the methods section. End aside.

However some trials do use the effective food admixture method. I found an innocent little study from 2013 which did just this:

Comparative evaluation of the efficacy of ginger and orlistat on obesity management, pancreatic lipase and liver peroxisomal catalase enzyme in male albino rats

It feels like a throwback to the 1950s. They generated their intervention (ground ginger, 5% by weight of the diet) by going to the local market in Cairo and buying some ginger, peeling it, washing it, mincing it and air drying it before milling it in to a fine flour to incorporate in to the diet. The comparator intervention was orlistat which they bought as capsules to be opened and incorporated in to the ration in a similar manner to the ginger.

The bottom line is that their ginger worked rather well compared to an unmodified high fat diet but sadly (for the ginger) the orlistat was incredibly effective, far more so than the ginger. This is why I got interested in the study. Not only did the rats on orlistat fail to grow, they had a marked increase in food intake. They ate a ton of high fat food yet put on remarkably little weight. There is no information provided about bowel function but I guess the rats on orlistat didn't wear underwear and they lived their lives metaphorically sitting on the loo. Certainly whenever they ate anything. Which was as often as possible.

The basic premise to orlistat is that if you take a drug which blocks fat absorption you decrease the functional "calories-in" so lose weight. Which is, of course, bollocks. What would actually happen is that you would eat more. You cannot fool your metabolism. You either eat more to meet your needs or you slow your metabolism to match your available calories. You feel cold, move as little as possible and dream about food. Most people would eat more.

This is what happened

Chow rats gained 60g, high fat fed rats gained 130g, orlistat treated high fat fed rats gained 7g. Seven grams. These rats did not want to be slim. They are not heading for the beach in a bikini. That low weight gain is malabsorption in action.

It causes hyperphagia because that is the only way the rats can even try to meet their caloric needs.

The implication of this study is that malabsorption makes you thin. That could be CICO. But orlistat malabsorption might also block linoleic acid absorption. That this might actually be true in real live people to facilitate a little genuine fat loss is where I was heading, but I lost interest when I tracked back through ref 17 to find that the high fat diet cited in this study is not obesogenic! Ref 17 as mentioned in:

"Group (2) G2: (High fat diet), rats of this group fed high fat diet (The diet contain 30% corn oil) according to Jacobs17"

A diet composed of 30% corn oil by weight, around 26% of calories from linoleic acid, is not obesogenic, in rats under the supervision of Jacobs.

Yet it clearly is obesogenic in Cairo.

Now that is interesting. These are thing which fascinate me. Ref 17 is next.

Peter