14 replies to this topic

[Adam Karlovsky]

I have not seen a thread on this research chemical yet, but it looks promising when looking at the effects on rats. 

 

From http://www.hopkinsme...f_heart_disease

 

• "Johns Hopkins scientists have halted the development of atherosclerotic heart disease in animals by blocking the activity of a sugar-and-fat molecule residing in the membranes of cells.
• Using a widely available man-made compound called D-PDMP, the researchers prevented the buildup of fatty plaque and calcium deposits inside the blood vessels of mice and rabbits fed a high-fat, cholesterol-laden diet.
• Treatment with D-PDMP appears to work by altering a range of biological glitches that affect the body’s ability to properly use, transport and purge itself of cholesterol — the fatty substance that accumulates inside vessels and fuels heart disease."

"D-PDMP, which is already widely used in basic research to experimentally block and study cell growth and other basic cell functions, is deemed safe in animals, the investigators say. For example, animals in the current study had no side effects even when given D-PDMP doses 10 times higher than the minimum effective dose, the study found. The research team is currently designing a compound drug with D-PDMP, which they soon plan to test in other animals and, eventually, in humans."

 

It sounds really interesting, no?

[mpe]

Sure does, I wonder if it works as well with an existing condition ?


Mike

[yates9]

What is P-PDMP?

 

 

 

[Adam Karlovsky]

http://circ.ahajourn...13.007559.short

 

 

Background—Glycosphingolipids are integral components of the cell membrane and have been shown to serve as messengers, transducing growth factor initiated phenotypes. Here we have examined whether inhibition of glycosphingolipid synthesis could ameliorate atherosclerosis and arterial stiffness in transgenic mice and rabbits.

Methods and Results—Apolipoprotein E-/- mice (12 weeks of age, n = 6) were fed regular chow or a western diet (1.25% cholesterol, 2% fat). Mice were fed 5mg/kg (mpk) or 10mpk of an inhibitor of glycosphingolipid synthesis, D-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (D-PDMP), solubilized in vehicle (5% Tween-80 in PBS) and the placebo group received vehicle only. At 20 and 36 weeks of age, serial echocardiography was performed to measure aortic intima medial thickening (IMT). Aortic pulse wave velocity (PWV) measured vascular stiffness. Feeding mice a western diet markedly increased aortic PWV, IMT, oxidized LDL, Ca²⁺ deposits, and glucosyl- and lactosylceramide synthase activity. These were dose-dependently decreased by feeding D-PDMP. In liver, D-PDMP decreased cholesterol and triglyceride levels by raising the expression of SREBP2, LDL-r, HMGCo-A reductase, and cholesterol efflux genes (e.g., ABCG5, ABCG8). D-PDMP affected VLDL catabolism by increasing the gene expression for LPL and VLDLr. Rabbits fed a western diet for 90 days had extensive atherosclerosis accompanied by a 17.5-fold increase in total cholesterol levels and a 3-fold increase in lactosylceramide levels. This was completely prevented by feeding D-PDMP.

Conclusions—Inhibition of glycosphingolipid synthesis ameliorates atherosclerosis and arterial stiffness in ApoE-/- mice and rabbits. Thus, inhibition of glycosphingolipid synthesis may be a novel approach to ameliorate atherosclerosis and arterial stiffness.

 

[bulky]

Does anyone know if this is a difficult compound to synthesize?

Would any of the compounding vendors produce it for sale?

Edited by bulky, 08 May 2014 - 06:06 PM.

[Adam Karlovsky]

Human dose equivalent (with the study I posted above as a dosing standard) is 0.8mg/kg.

 

It might be best to ask about getting a grant for a safety testing study of this chemical. Something simple like a sample of 50 standard rats, some control, test for major markers of health (brain, liver, heart), and see what all-death mortality rates are. Then when we have some mortality results we can think about a group buy, if that is what you were thinking about.

 

To give people an introduction into this chemical of topic... http://www.ncbi.nlm....pubmed/20919653

 

 

 

Glucosylceramide has a unique and often ambiguous role in mammalian cells. Activation of glucosylceramide synthase, the enzyme that places a glucosyl moiety onto ceramide, is the first pathway-committed step to the production of more complex glycosphingolipids such as lactosylceramide and gangliosides. Alterations in the level of glucosylceramide are noted in cells and tissues in response to cardiovascular disease, diabetes, skin disorders and cancer. Overall, upregulation of glucosylceramide offers cellular protection and primes certain cells for proliferation. However, prolonged overabundance of glucosylceramide is detrimental, as seen in Gaucher disease in humans.

 

http://www.google.co...tents/US5041441

 

 

 

The injection of glucosylceramide into mice has been shown to produce marked, rapid stimulation of the growth of the liver (which preferentially absorbs the lipid). In the case of mice bearing Ehrlich ascites carcinoma cells, the injection of glucosylceramide resulted in a greater than 50% increase in the number of cancer cells. Recent studies have also indicated that patients with Gaucher's disease, which results from an accumulation of glucosylceramide, have an unexpectedly high incidence of leukemia and other B-cell proliferation disorders.

 

 

In accordance with the present invention, cancer cells sensitive to glycosphingolipid metabolism inhibition are treated by contacting the cells with an inhibitor which interferes with the metabolic pathways of glycosphingolipids. The inhibitor can function by blocking the enzymatic synthesis of glycosphingolipids, particularly glucosylceramide and its derivatives, hereinafter collectively referred to as "glucolipids," or by blocking other physiological processing thereof such as their transport.

In addition, the method of the present invention can be used to treat non-malignant conditions caused by cell proliferation such as benign tumors, warts, skin growths and the like. The method of the present invention may also be used to prevent fetal development and terminate undesired pregnancies.

 

 

 

Male mice of the ICR (Swiss Hsd) strain from Harlan--Sprague Dawley (Indianapolis, Ind.) were injected intraperitoneal with saline containing 2×10⁶ Ehrlich ascites tumor cells (EATC) on day 0....

Column (a) indicates the low drug toxicity. Column (b), which shows the change in mean body weight at the end of 10 days, indicates the drug toxicity as evidenced by subnormal weight gain...

A dose response test of D-threo-PDMP showed that the T/C index increased with increasing dosage, as did the percentage of total cure. All animals injected with 25 or 50 mg/kg died at about the same time as the controls, although the drug reduced the chance of early death. The percentages surviving for 60 days were 10%, 20% and 50% for 75, 100, and 125 mg/kg, respectively. After more than 5 months after inoculation, 40% of the two most-heavily dosed mouse groups were still alive and healthy.

 

So basically D-threo-PDMP has been patented as a potential treatment for some types of cancers, because it also lowers cell proliferation. It didn't seem to effect total mortality, but reduced the risk of early death.

[Adam Karlovsky]

 

 

Experiment 4

Ten normal, noncancerous mice were injected with D-threo-PDMP daily for 10 days, then killed 5 hours later with the results set forth in Table 4. 

 

The control mice gained an average of 4.5 g while the treated mice gained 2.1 g. The treated mice had distinctly smaller weights: 8% in bodies, 18% in livers, and 17% in kidneys. The spleens were slightly but not significantly smaller and the brains were 4.6% smaller (p less than 0.025). Using the data for percent of body weight, to minimize the importance of general toxicity, only the livers and kidneys were significantly smaller (p less than 0.05%). The above decreases in organ size were in the direction expected from a diminished level of tissue glucosylceramide, since injection of the latter produced liver growth.

 

This experiment shows we should be careful, if it can potentially reduce brain size then we should study the changes in functioning of the brain. A smaller brain from treatment of D-PDMP may not be inherently less functional, but it does suggest that it might be. 

 

 

 

Cell counts made on orbital blood showed no abnormalities in RBC, WBC, differential monocytes, lymphocytes, eosinophiles, and neutrophils. This failure to harm the bone marrow and related systems compares favorably with the high toxicity of many antineoplastics.

 

As far as general safety goes, there are "no abnormalities in RBC, WBC, differential monocytes, lymphocytes, eosinophiles, and neutrophils"

 

 

 

Four mice who had survived 63 days post-inoculation were challenged with another 2×10⁶ EATC. These mice showed no effects of the reinoculation for greater than 7 months more. Five other survivors were challenged 135 and 100 days after inoculation and four of them developed no EATC for greater than 5 months of observation. Normal mice of this age, like the younger ones, are readily attacked by EATC. We conclude that the mice have, in effect, been "live-cell vaccinated" with EATC plus PDMP.

 

Interestingly we see there is a 'vaccination' potential with proper chemotheraputic use of PDMP. This goes far beyond what we might use it for, but it is cool none the less.

 

[Adam Karlovsky]

Links for further reading, I don't want to clog up this thread:

http://assets.cureus...inch_UPDATE.pdf

http://www.jbc.org/c...0/26/24515.full

http://atvb.ahajourn.../5/931.full.pdf

[Adam Karlovsky]

https://www.jstage.j..._3_195/_article

 

In the present study, D-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (D-PDMP), a glucosylceramide synthase inhibitor, completely inhibited osteoclastogenesis induced by macrophage-colony stimulating factor (M-CSF) and receptor activator of NF-κB ligand (RANKL). Following treatment with D-PDMP, nearly all glycosphingolipid expression was dramatically reduced on the surface of bone marrow cells, which suggests that glycosphingolipids are necessary for osteoclastogenesis. 

 

 

An osteoclast is a type of bone cell that resorbs bone tissue. This function is critical in the maintenance and repair of compact bones in the mammalian skeleton. We need to find out the safety issues linked to having too few osteoclasts... but having said that... D-PDMP may have application in stopping or reversing osteoperosis?

[bulky]

I know the people on this board sometimes obtain compounded versions of chemicals for testing...  are you saing the first step is to apply for a grant? I personally do not have a lab or mice for testing, I'd be glad to contribute to such an effort but I doubt a grant would be bestowed to me. I would think there would be a clamour for D-PGMP given the good press.

 

[solbanger]

Hi there,

 

Tiny follow up to this interesting topic. Looks like scientists have finally perfected a delivery method for mammals with incredible results! They accomplished this by wrapping the D-PDMP with nanoparticles of sebacic acid and a laxative. It made the delivery of the chemical much more effective. So much so that rats given the nanowrapped version had their atherosclerosis practically disappear after months of eating a high fat diet. Rats given D-PDMP in its natural form needed 10 times the dose to show any improvement, the reason being that their bodies appeared to flush it out much faster than normal. Next step is to test it on larger animals. Anyone here want to volunteer? Lol. 

 

I think this is a huge step in addressing heart disease and other types of cardiovascular blockages that show up in old age. I imagine this will eventually be applied to humans as part of a regular check up along with their flu shot and blood pressure. The nurse simply injects you with PDMP and voila, no need to worry about that steak you just had!

 

We might be on the verge of getting a biomedical version of drano very soon.

 

http://www.hopkinsme...rodent_arteries

Edited by solbanger, 15 August 2015 - 01:31 AM.

[solbanger]

The last update I saw of this was in June 2015

 

http://www.upi.com/H.../1911435162063/

 

 

[Daniel Cooper]

Anyone know if there has been further development on this?

 

Has the safety of D-PDMP been established in humans?  If so, this might be interesting to experiment with, even without the fancy nanoparticle wrapper that the Johns Hopkins people are doing.

 

 

 

[saxxie]

https://www.genengne...9675b9130356b7s

[dalack]

Who would be interested in getting some of this compound synthesized?